DEPARTMENT OF
 MOLECULAR GENETICS,
     MICROBIOLOGY
     & IMMUNOLOGY


     ANNUAL REPORT
JULY 1, 2005 - JUNE 30, 2006

...
Table of Contents
Preface ...................................................................................................
Evelyn S. Erenrich ...................................................................................................... ...
Honghua Li, Ph.D. .................................................................................................... 157...
PREFACE




        During the past year, the faculty of the department has maintained its high level
of performance in re...
INTRODUCTION


      By their activities in research, teaching, and service to the medical school the
University, and the ...
of Health or other governmental agencies.

         The department has played a very important role in the training and re...
Molecular Genetics, Microbiology and Immunology serves as a shared resource for
faculty of Robert Wood Johnson Medical Sch...
In the department core facilities, Zofia Andes, Principal Laboratory Assistant, and
May Tang, Laboratory Service Worker, w...
.Research      Activities

     The research activities in the department continue to open up new areas.
Some highlights a...
Drug-carrying bioconjugates based on polyethylene glycol can be synthesized
with attached ligands for cell surface recepto...
On May 3, 2006 at the Museum of Contemporary Art in Chicago Dr. Pestka
received the Lemelson-MIT Lifetime Achievement Awar...
Dr. Stollar demonstrated that the size of the UTP and CTP pools in mosquito
cells, as modified by PZF and uridine, determi...
PERSONNEL

Faculty
Gary Brewer, Ph.D., Professor
Paul Copeland, Ph.D., Assistant Professor
Joseph P. Dougherty, Ph.D., Pro...
Joint Appointments, Cont'd
Randall D. McKinnon, Ph.D., Associate Professor of Surgery and Molecular Genetics,
   Microbiol...
Volunteer Adjunct Faculty, cont'd
Fred Mermelstein, Ph.D., Adjunct Assistant Professor
Margaret Prescott, Ph.D., Adjunct A...
Research Associates, Postdoctoral
Appointees                          Full-time Laboratory Staff
Xiangfeng Cui, Ph.D.     ...
DEPARTMENTAL ACTIVITIES

Appointments
Stephane Gross, Ph.D., Appointment as Adjunct Professor of Molecular Genetics,
     ...
DEPARTMENTAL COMMITTEES

                           Vice Chairman
                             Victor Stollar



Standing ...
Activities of

     MGMI

Faculty Members

   2004-2005
Gary Brewer, Ph.D.
Research Activities
Dr. Brewer’s research involves the study of proto-oncogene and cytokine messenger
R...
Posttranscriptional Gene Expression, NY Academy of Sciences, New York, NY.

“AUF1: Where nonsense-mediated meets ARE-media...
Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists
Rutgers Undergraduate Research in Biology/Genetics & Micr...
Member, Departmental Seminar Committee
Member, Retreat Committee, Department of Molecular Genetics, Microbiology, &
    Im...
Paul R. Copeland, Ph.D.
Research Activities
Incorporation of selenocysteine
        Selenocysteine is a unique amino acid ...
selenoprotein pathway, then prostate cancer cells are likely to have altered
selenoprotein expression. Indeed, it has been...
selenocysteine in mammals. Nucl Acid Res. 33:5172-5180.

Caban, K. and Copeland, P.R. (2006) Size matters: a view of selen...
Holowczak Memorial Committee
Chairman, Department Website Committee

RWJMS
Research Day Committee
Member, Molecular Biosci...
RNA
Nucl. Acid. Res.
Joseph P. Dougherty, Ph.D.
Research Activities
Research in our laboratory focuses upon studying retroviral replication as ...
being transduced into infected cells, resulting in a quantitative assay representing the
entire viral life cycle in a sing...
activation downstream of any proviral integration site does not occur. In order to prevent
regeneration of fully intact LT...
that all retroviruses including HIV are always subject to crossovers during each
      and every cycle of replication indi...
Florence LeRoy
Sofiya Micheva-Viteva
Sayandip Mukherjee
Annmarie Pacchia
Bradley Phelan
Danny Tu Khounh
Jiang Xi
Jiangling...
Donald T. Dubin, M.D.
Research Activities
Dr. Dubin has stopped active laboratory research. He continues to follow the cur...
Terri Goss Kinzy, Ph.D.
Research Activities
       The goal of the work in the Kinzy laboratory is to understand the struc...
integrated with above work to fully dissect the mechanisms of protein synthesis and to
better understand their potential a...
Pittman, Y., Valente, L., Jeppesen, M.G., Andersen, G.R., Patel, S. and Kinzy, T.G.
      Biochemical and Mutational Analy...
Seminars Sponsored
Christopher Hellen, SUNY Downstate, 2/14/06 Mechanisms of translation initiation by
       internal rib...
Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists
Postdoctoral Appointees: Monika Anand Ph.D., Stephane Gro...
RWJMS Master Educators Committee
NIEHS Center of Excellence Pilot Grant Review Committee
Foundation of UMDNJ RWJMS Grant R...
Jerome Langer, Ph.D.
Research Acitivities
        Dr. Langer continues work funded by the Alliance for Lupus Research dire...
Teaching
Microbiology & Immunology (RWJMS) (Spring 2006) Laboratory instructor.
Molecular Virology, Lecturer (Spring 2006)...
Member.
Molecular Biosciences Graduate Programs, Rotation advisory committee, Member
Molecular Biosciences Graduate Progra...
Michael J. Leibowtiz, M.D., Ph.D.

Research Activities

Beta-sheet blockers as therapeutic agents
In collaboration with Dr...
Wan, L., Zhang, X., Gunaseelan, S., Pooyan, S., Debrah, O., Leibowitz, M.J., Rabson,
      Arnold B., Stein, S., Sinko, P....
Meetings Attended

November 2-5, 2005, represented UMDNJ–GSBS and RWJMS at the Annual
      Biomedical Research Conference...
Odette Williams, Livingston College.
Ralitza Varlakova, Rutgers College.
Andrei Nesterov, Rutgers College.
Christina Hanse...
Member, Piscataway Campus Summer Program Directors
Member, Advisory Committee for the UMDNJ Presidential Search. (July, 20...
Honghua Li, Ph.D.
Research Activities

Research Activities
Our laboratory is interested in understanding the molecular mec...
recombinants. The crossovers were nonrandomly distributed within 16 small areas. All,
except one, of these crossovers fall...
DEPARTMENT OF MOLECULAR GENETICS, MICROBIOLOGY
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DEPARTMENT OF MOLECULAR GENETICS, MICROBIOLOGY
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DEPARTMENT OF MOLECULAR GENETICS, MICROBIOLOGY
DEPARTMENT OF MOLECULAR GENETICS, MICROBIOLOGY
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  1. 1. DEPARTMENT OF MOLECULAR GENETICS, MICROBIOLOGY & IMMUNOLOGY ANNUAL REPORT JULY 1, 2005 - JUNE 30, 2006 SIDNEY PESTKA, M.D. PROFESSOR AND CHAIRMAN
  2. 2. Table of Contents Preface ............................................................................................................................................ 1 Introduction .................................................................................................................................... 2 Research Activities ........................................................................................................................ 5 Personnel........................................................................................................................................ 9 Departmental Activities ............................................................................................................... 13 Departmental Committees .......................................................................................................... 15 Activities of the Faculty Members.............................................................................................. 16 Gary Brewer, Ph.D. .................................................................................................... 17 Paul R. Copeland, Ph.D. ............................................................................................ 21 Joseph P. Dougherty, Ph.D........................................................................................ 26 Donald T. Dubin, M.D. ................................................................................................ 31 Terri Goss Kinzy, Ph.D. .............................................................................................. 32 Jerome Langer, Ph.D. ................................................................................................ 38 Michael J. Leibowitz, M.D., Ph.D................................................................................ 41 Honghua Li, Ph.D. ...................................................................................................... 46 Michael Newlon, Ph.D. ............................................................................................... 49 Stuart W. Peltz, Ph.D.................................................................................................. 50 Sidney Pestka, M.D., Chairman ................................................................................. 51 Arnold B. Rabson, M.D............................................................................................... 59 Yacov Ron, Ph.D. ....................................................................................................... 65 Aaron J. Shatkin, Ph.D. .............................................................................................. 67 Yufang Shi, D.V.M., Ph.D. .......................................................................................... 71 Victor Stollar, M.D., Vice Chairman............................................................................ 77 Nancy Woychik, Ph.D................................................................................................. 80 Research Activities of Joint and Adjunct Faculty .................................................................... 84 Sefik S. Alkan, Ph.D. .................................................................................................. 85 Eddy Arnold, Ph.D. ..................................................................................................... 87 David Beck, Ph.D. ...................................................................................................... 90 C. Thomas Caskey, M.D. ........................................................................................... 90 Chiann-Chyi Chen, Ph.D. ........................................................................................... 90 Graham Cleaves, Ph.D............................................................................................... 91 Ellen C. Ebert, Ph.D.. ................................................................................................. 92
  3. 3. Evelyn S. Erenrich ...................................................................................................... 93 Arthur M. Felix, Ph.D. ................................................................................................. 95 Janusz J. Godyn, M.D. ............................................................................................... 96 Suhayl Dhib-Jalbut, M.D........................................................................................... 100 Edmund C. Lattime, Ph.D......................................................................................... 102 Paola Leone, Ph.D. .................................................................................................. 106 Mei-Ling Li, Ph.D. ..................................................................................................... 108 Randall D. McKinnon, Ph.D...................................................................................... 109 M. Maral Mouradian, M.D. ........................................................................................ 111 Daniel Notterman, M.D. ............................................................................................ 114 Michael Reiss, M.D................................................................................................... 117 Hugh Rosen, Ph.D.................................................................................................... 119 Srijata Sarkar, Ph.D.................................................................................................. 120 Lee Ann Schein, Ph.D. ............................................................................................. 121 Leonard H. Sigal, M.D. ............................................................................................. 123 Michael Steinmetz, Ph.D. ......................................................................................... 124 George B. Weiss, Ph.D. ........................................................................................... 125 Lawrence P. Wennogle, Ph.D. ................................................................................. 125 Carol Wilusz, Ph.D. .................................................................................................. 125 Core Facilities............................................................................................................................. 128 Doctoral Program....................................................................................................................... 131 Courses .................................................................................................................................. 134 Microbiology for Physician Assistants ...................................................................... 135 Medical Genetics ...................................................................................................... 139 Medical Microbiology and Immunology .................................................................... 143 Holowczak Memorial Fund........................................................................................................ 148 Research Grant Support ........................................................................................................... 149 Gary Brewer ............................................................................................................. 150 Paul R. Copeland, Ph.D. .......................................................................................... 151 Joseph P. Dougherty, Ph.D...................................................................................... 152 Terri Goss Kinzy, Ph.D. ............................................................................................ 153 Jerome Langer, Ph.D. .............................................................................................. 155 Michael J. Leibowitz, M.D., Ph.D.............................................................................. 156
  4. 4. Honghua Li, Ph.D. .................................................................................................... 157 Mei-Ling Li ................................................................................................................ 158 Sidney Pestka, M.D., Chairman ............................................................................... 159 Arnold B. Rabson, M.D............................................................................................. 160 Yacov Ron, Ph.D. ..................................................................................................... 161 Yufang Shi, D.V.M., Ph.D. ........................................................................................ 162 Victor Stollar, M.D., Vice Chairman.......................................................................... 163 Nancy Woychik, Ph.D............................................................................................... 164 Summary of Outside Grant Support ......................................................................... 165 Seminars .................................................................................................................................. 166 Departmental Retreat................................................................................................................. 167 Departmental Organization Chart............................................................................................. 169
  5. 5. PREFACE During the past year, the faculty of the department has maintained its high level of performance in research, in teaching, and in service to the University community. Although the funding environment has been difficult, grant support in the department from national and non-governmental sources has continued at a good level. The total number of grants in the department was XXXXX. Many of the faculty are invited to lecture at other institutions, as well as at national and international symposia. Faculty also sit on review committees for the National Institutes of Health and for the Department of Defence. Publication in top level peer-reviewed journals also continues at a good level. Core facilities developed in the department have been made available to the broader University communities both at RWJMS and at Rutgers University. These include the DNA Synthesis and Sequencing Facility, and a Cell Imaging Facility. Both of these facilities are being continually upgraded. As well, in order to analyze specific protein-protein interactions in cells, equipment was constructed to carry out analysis of fluorescence energy transfer in single cells in real time. All of the faculty are active in teaching in either the medical school course for first year medical students, in graduate courses, or both. Graduate courses in virology and immunology directed by members of this faculty are the only such offerings in these fields on this campus. The medical school course is very well received by the medical students. One of the largest programs in the nation for the recruitment and training of under represented minority students is centered here at RWJMS and is under the direction of Drs. Michael Leibowitz, Jerome Langer, and Evelyn Erenrich, all of whom are members of this department. These programs are supported by two major grants from the National Institutes of Health. Many members of the department also serve on important committees of RWJMS or UMDNJ. Especially notable during the past year was the expansion of the MD/PhD program of which Dr. Terri Kinzi is director. These topics are all developed at greater length in the Annual Report.
  6. 6. INTRODUCTION By their activities in research, teaching, and service to the medical school the University, and the broader scientific community, the faculty of the department continue to make impressive contributions to the missions of RWJMS, and UMDNJ. The full time tenured or tenure-track faculty consists of 13 full professors, 3 associate professors, and 2 assistant professors. In addition there are 6 non-tenure track faculty including 6 adjunct assistant professors. Although the competition for research grants has, in the last few years, become quite difficult, the members of the department continue to do well in obtaining research support from federal agencies, from the State of New Jersey, as well as from non- governmental sources. Total funding for this academic year was ???????, and the total number of grants was XXXX . Forty-seven papers were published in peer-reviewed journals by the department faculty during the past year. The research interests of the faculty, as shown by the titles of the grants which have been awarded, are very broad and illustrate the wide range of their interests. These include protein synthesis, control of gene expression as manifest by the stability of mRNAs, the mode of action of interferons and other cytokines with emphasis on the signaling pathways which they activate, autoimmune diseases, apoptosis, virology, oncology, and bacterial toxins. Many in the department are involved in collaborative projects with other faculty in the department, or outside the department. All members of the department are involved in teaching either in the Microbiology and Immunology course taught to first year medical students or in a wide variety of graduate courses. The medical school course is well received by the medical students, and many compliments are paid to Dr. Michael Newlon, who is director of the course. Dr, Newlon continues to add web-based instruction, visual resources, and interactive quizzes to the course. Each year our medical students perform very well on the Microbiology section of the National Board exams, part I. Members of the department also play important administrative roles in RWJMS. Dr. Aaron Shatkin is Director of the Center for Advanced Biotechnology and Medicine (CABM). Dr. Arnold Rabson is Deputy Director of the Cancer Institute of New Jersey (CINJ), and also chairs the Appointments and Promotions Committee of RWJMS. Dr. Michael Leibowitz is Associate Dean of the Graduate School of Biomedical Science (GSBS) of UMDNJ at RWJMS. Dr. Terry Kinzy is director of the MD/PhD program which now encompasses not only RWJMS and Rutgers University, but also Princeton University. Dr. Joseph Dougherty is Director of the Graduate Program in Molecular Genetics, Microbiology, and Immunology, which includes faculty of both RWJMS and Rutgers University. Many members of the department also serve the broader scientific community by serving on the editorial board of journals, and on review panels at the National Institutes
  7. 7. of Health or other governmental agencies. The department has played a very important role in the training and recruitment of under-represented minority students. Dr. Leibowitz, in collaboration with Drs. Jerome Langer and Evelyn Erenrich is the Program Director of three NIH awards promoting training of minority graduate students on the Piscataway/New Brunswick campuses of RWJMS and Rutgers University. These include an Initiative to Maximize Student Diversity Award from NIH, which is now in its third four-year funding period, and provides $430,000 per year for support of the UMDNJ-Rutgers University Pipeline Program. This program supports Ph.D. and M.D.Ph.D. candidates as well as supervised individual research experiences for medical students. In addition to the Pipeline Program, the NIH-funded Bridge to the Doctoral Degree Program supports two articulated MS/PhD Programs on this campus. One, run jointly with the University of Puerto Rico, Mayagüez campus, is in its third funding period. An additional Bridge Program with Montclair State University is now in its second funding period. Dr. Erenrich, together with Dr. Langer, also directs the summer “Research in Science and Engineering (RISE) Program” at Rutgers/UMDNJ, which is currently funded by Rutgers University and by grants from corporate sponsors and the Federation of American Societies for Experimental Biology (FASEB). This is a nationally recognized outreach program, nearly half of whose alumni have gone on to Ph.D. and M.D./Ph.D. programs here and elsewhere, and which is a major source of recruitment of outstanding graduate students to this campus. UMDNJ and Rutgers University also participate in the Northeast Alliance for Graduate Education and the Professoriate, a consortium of research intensive universities in the Northeast and minority-serving undergraduate institutions, which is funded by the NSF. This consortium is a major support of recruitment and bridge programs on this campus, with Dr. Erenrich and Dr. Leibowitz serving as liaisons with Rutgers University and with the University of Massachusetts, to which the grant is awarded. Dr. Victor Stollar is Vice Chairman of the department. He assists the department chairman as is necessary, and is always available for advice and consultation on all matters which bear on the functioning of the department, both internal and those which relate to the role of the department in the medical school. Dr. Stollar often substitutes for the chairman at various functions, when the chair has scheduling conflicts. The annual department retreat was held on August 26, 2005, at the Hilton Garden Inn in Bridgewater, New Jersey. The goal of the retreats is to give graduate students and postdoctoral fellows an opportunity to present their work in a formal setting. In addition, the retreat serves to inform every one of the research activities of the other groups in the department. Not least, the retreats help promote good interactions and relationships within the department. Each research group gives one 12 minute presentation which is followed by a question and answer period. The program of the retreat is provided later in this report. In most years, the formal part of the retreat is followed by a buffet style lunch. The DNA Synthesis and Sequencing Core Facility of the Department of
  8. 8. Molecular Genetics, Microbiology and Immunology serves as a shared resource for faculty of Robert Wood Johnson Medical School and Rutgers. In addition this facility provides core resources for two joint institutes of RWJMS and Rutgers, the Cancer Institute of New Jersey (CINJ) and The National Institute of Environmental Health Sciences (NIEHS) Center at the Environmental and Occupational Health Sciences Institute (EOHSI). The overall purpose of this shared resource is to provide a centralized, high quality, cost-effective facility for DNA synthesis and sequencing for use by the entire scientific community at UMDNJ-RWJMS and Rutgers University. By providing synthetic oligonucleotides to all members of the University, many studies are greatly facilitated at significant cost discounts over what individual laboratories could obtain. Terri Goss Kinzy, Ph.D., Professor of Molecular Genetics, Microbiology and Immunology is Executive Director of this facility and Lee Ann Schein, Ph.D., is Director. This is one example where departmental resources have been used to develop a core facility that is essential for the scientific development of RWJMS. Mr. Rick Wernoski is the Business Manager of this facility. DNA Microarray Facilities were initiated from a shared instrumentation grant received by Dr. Pestka. A portion of the funds were used to establish the facilities at the CINJ in New Brunswick and in Piscataway to make it most accessible to investigators in both locations. The facility in Piscataway includes a Phosphorimager for analysis of the DNA microarrays. This is a shared facility open to investigators of RWJMS, Rutgers and all members of the UMDNJ community. We have also opened it up to outside academic and commercial institutions to facilitate collaborations and general research programs in New Jersey. This facility is used extensively. With the departure of Dr. Jeffry Cook, Dr. Gary Brewer is now the Director of the facility. This is a second example where departmental resources are used to support the scientific development of RWJMS, Rutgers and UMDNJ. Mr. Rick Wernoski is also the Business Manager of this facility. The department faculty are very ably assisted by an efficient office staff, who when called upon in special situations, give that extra effort which is often necessary and crucial. Rick Wernoski, MPA, Business Manager, was responsible for all day-to- day operations of the department including financial, administrative, staffing and facility needs until he left the department in May, 2006. Ellen Feibel, Senior Management Assistant, under the supervision of the department chairman, performs a wide variety of administrative and secretarial services. Jamie Carr, Administrative Analyst, was responsible for grant administration. Walter Barnes, Budget Analyst III, was responsible for maintaining, reviewing, and analyzing the departmental accounts. Andrea Finamore, Administrative Coordinator II, performed Human Resources services and assisted with the administrative activities of the department. Rosalie Reina, Program Assistant, served as the primary contact for undergraduate trainees involved in the UMDNJ- Rutgers University Pipeline Program and in coordinating the administrative functions related to the training grant “Virus-Host Interactions in Eukaryotic Cells”. Toni Thomas, Secretary IV, assisted departmental staff with administrative and secretarial services until her retirement in August of 2005.
  9. 9. In the department core facilities, Zofia Andes, Principal Laboratory Assistant, and May Tang, Laboratory Service Worker, were responsible for washing and sterilizing glassware. Octavia Gamble, Laboratory Assistant, prepared agar plates for growth of bacteria and yeast, as well as sterile tissue culture media, and various solutions used in different laboratories. In summary, by its activities in research, teaching, and administration, the department continued to make a strong contribution to the missions of RWJMS. Those activities dedicated to the training of scientists and physicians have always been considered especially important to the faculty.
  10. 10. .Research Activities The research activities in the department continue to open up new areas. Some highlights are given below; details are provided in a later section. Dr. Brewer’s laboratory published two seminal papers regarding regulation of genes involved in genotoxic stress responses and in breast cancer. These papers identify the RNA-binding protein AUF1, which we discovered in 1991, as a critical regulator of the GADD45α (genotoxic stress) and c-Yes (kinase involved in breast cancer) genes. Dr Copeland’s laboratory continues their investigation into the mechanism of selenocysteine incorporation as well into the larger questions that probe the balance between selenium efficacy and toxicity. Dr. Dougherty carried out a high throughput screen which has provided lead molecules that can be used to develop drugs to clear HIV-1 latent infection and that can be used as probes to study HIV-1 latency. He developed a very efficient and safe HIV-2 lentiviral vector system for gene transduction. He and his staff discovered that the recombination rate of disparate retroviruses is very high suggesting that all retroviruses including HIV are always subject to crossovers during each and every cycle of replication indicating that the basic model of retroviral reverse transcription should be modified. In Dr. Kinzy’s Laboratory their understanding of the role of the translation elongation factor 1A (eEF1A) has extended beyond its canonical role in delivery of aminoacyl-tRNA for elongation. They have published novel mutants that separate the actin and translation functions of eEF1A, providing a new example of a multifunctional protein and a link between the translational apparatus and regulation of the actin cytoskeleton. Additionally, the regulation of the levels of eEF2, the translocase, and the novel effect of dominant negative mutants on the cell were determined.. Dr. Langer found that alpha interferon appears to be inappropriately, perhaps continually, produced in people with systemic lupus erythematosus (“lupus”), and that this aberrant production of IFN likely contributes to the pathogenesis of this disease. To block the effects of IFN in lupus patients, He and his laboratory are designing and produceing modified IFNs that should act as competitive antagonists of endogenous IFN. They have investigated several parts of the IFN molecule for their importance in interactions with the 2 subunits of the IFN receptor. They demonstrated that a region of IFN previously reported to be important in one IFN subtype for receptor interactions does not make strong contributions to receptor interactions in the IFN subtype used in our lab. They have therefore proposed a novel model of IFN/receptor interactions, and are examining the effects of mutations in other parts of the IFN molecule.
  11. 11. Drug-carrying bioconjugates based on polyethylene glycol can be synthesized with attached ligands for cell surface receptors to target the conjugates to cells bearing those receptors, to which the drugs can then be delivered with great specificity. Dr. Leibowitz has shown that multiple copies of formyl-methionyl-leucyl-phenylalanine attached to the bioconjugates can greatly enhance their delivery to macrophages. This finding has great potential for developing drug delivery systems for these cells, which are the primary infected cell type in AIDS and tuberculosis. Dr. Li has made significant progress toward further extending the application of his high-throughput nucleic acid detection system. This system has been used for studying meiotic recombination in great detail and on a large scale. He has also used it for studying genetic variation in breast cancer tissues and cell lines, and in colon cancer. He has been very successful in using this marker system, for the first time, to detect meiotic recombination along entire chromosomes and to locate meiotic crossover points for understanding the mechanisms underlying meiotic recombination. He has also made significant progress in understanding the genetic structure of the human immunoglobulin VH region. This finding may have significant impact on understanding the contribution of the genetic structure of the VH region to the function of the immune system. In collaboration with other M-1 course directors and other interested faculty, Dr. Newlon planned and implemented a new course “M-1 Integrated Cases” designed to show how material from all first-year courses relates to specific medical cases. Each case began with a lecture-hall presentation which was followed by a small-group team- based learning exercise. This year seven cases were presented: Ethylene glycol poisoning, Duchenne muscular dystrophy, Marfan syndrome, alpha-1 antitrypsin deficiency, meningococcal meningitis, subacute bacterial endocarditis, and polycystic kidney disease. Dr. Newlon was chief author of two of the cases. Dr. Newlon was awarded an Educational Technology Advisory Committee to fund creation of visual resources for teaching medical bacteriology, which will become part of the MGMB 6000 Microbiology and Immunology course web site, and began developing these materials. Dr. Peltz has been on a leave of absence beginning November 2004 and continuing through December 2006. The work of his lab is now under the supervision of Dr. Joseph Dougherty. Dr. Pestka in this year discovered dscovered that the IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix and is dependent on N-linked glycosylation. He and his laboratory staff discovered PRMT9, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. They also discovered new Class 2 cytokines and receptors in many vertebrates and in humans, including new interferons as well as the discovery that IL-10 receptor chains are preassembled.
  12. 12. On May 3, 2006 at the Museum of Contemporary Art in Chicago Dr. Pestka received the Lemelson-MIT Lifetime Achievement Award for his seminal work on interferons. As stated by the Lemelson-MIT Program, “his work led to groundbreaking treatments for chronic hepatitis B and C, multiple sclerosis and cancers. The annual award, which recognizes a remarkable individual for his or her life-long commitment to improving society through invention.” “Dr. Pestka’s interferon discoveries and subsequent inventions have made a profound impact on medicine and health care,” said Merton Flemings, director of the Lemelson-MIT Program, which gives the annual award. “His work has opened doors to new treatments for millions of people who suffer from devastating diseases and it has fueled the multi-billion dollar biotherapeutics market.” On May 4, 2006 Dr. Pestka was honored with the Researcher Leader award by the New Jersey High Tech Hall of Fame. Dr. Rabson’s laboratory has further delineated a pathway for activation of latent HTLV-1 through T-cell receptor activation. This result provides a possible mechanism for the pathogenesis of HTLV-1-induced diseases, in particular, Adult T-cell leukemia (ATL) which is currently being explored in transgenic mice in order to develop a small animal model of this devastating leukemia. His laboratory has also identified genes that are critical for the development of a second human T-cell malignancy, cutaneous T-cell lymphoma, and is currently further characterizing these genes. Dr. Ron has used retroviral tagging to identify a myeloid precursor cell population in mouse spleen that can give rise to the whole myeloid system. This population is long-lived and will reconstitute the myeloid system for at least six months. Dr. Shatkin documented the essential role of mRNA capping in mammalian cells and the consequences of its disruption. Dr. Shi has made significant progress in several areas. He has made significant advancement in the understanding of the role of granzyme B in the regulation of AICD in different T cell populations. Mice deficient in granzyme B develop more severe allergic asthma. Importantly, they have found that CD4+ T cells are solely responsible for allergen-induced asthmatic reaction. Furthermore, through genetic modifications, Dr. Shi’s group found that MHC class Ib restricted CD8+ T cells are critical in the development of autoimmunity. They also made significant progress in the understanding of the mechanisms that regulate RANKL expression in T cells. Their new in vivo and in vitro system provided a unique opportunity to study how apoptotic cells regulate the immune response. The establishment of the mesenchymal stem cell project gives Dr. Shi’s group a unique niche to using their immunology expertise to investigate the mechanisms controlling mesenchymal stem cell-mediated immunosuppression; it is also hoped that their efforts in this direction will provide new information for proper clinical application of these cells. His project on stress and radiation has been focused on the development of new countermeasures in response to the directional changes in NASA research.
  13. 13. Dr. Stollar demonstrated that the size of the UTP and CTP pools in mosquito cells, as modified by PZF and uridine, determine not only the yield of the mutant, SVpzf, but also the ratio of SG/G RNA which is made in the SVpzf-infected cells. Thus the frequency of initiation at the SVpzf SG and G promoters may be influenced by the size of the UTP pool in the infected cells. He also is working on the development of cell-free systems for the synthesis of SV RNAs. Dr. Woychik has completed characterization of the function of one bacterial TA toxin, designed Doc. Doc leads to inhibition of bacterial cell growth by specifically binding to the bacterial 30S ribosome that leads to inhibition of translation elongation. We have also made considerable progress on understanding the structure and function of several other TA toxins. The structure of the antitoxin HigA has been completed and deposited into PDB (in collaboration with the Hunt laboratory, Columbia University).
  14. 14. PERSONNEL Faculty Gary Brewer, Ph.D., Professor Paul Copeland, Ph.D., Assistant Professor Joseph P. Dougherty, Ph.D., Professor Donald T. Dubin, M.D., Professor Terri Goss Kinzy, Ph.D., Professor Jerome A. Langer, Ph.D., Associate Professor Michael J. Leibowitz, M.D., Ph.D., Professor Honghua Li, Ph.D., Associate Professor Michael Newlon, Ph.D., Assistant Professor Stuart W. Peltz, Ph.D., Professor Sidney Peskta, M.D., Professor and Chairman Yacov Ron, Ph.D., Professor Yufang Shi, DVM, Ph.D., Professor Victor Stollar, M.D., Professor Nancy Woychik, Ph.D., Associate Professor Faculty Resident at CABM Arnold B. Rabson, M.D., Professor Aaron J. Shatkin, Ph.D., Professor Faculty (Coterminus) Philip Furmanski, Ph.D., Professor Emeritus Professors William A. Strohl, Ph.D., Emeritus Professor Joint Appointments Bruce C. Byrne, Ph.D., Adjunct Professor of Medicine and Molecular Genetics, Microbiology and Immunology Kiron M. Das, M.D., Ph.D., F.R.C.P., Professor of Medicine and Molecular Genetics, Microbiology and Immunology Ellen C. Ebert, M.D., Associate Professor of Medicine and Molecular Genetics, Microbiology and Immunology Janusz J. Godyn, Ph.D., Associate Professor of Pathology and Laboratory Medicine and Molecular Genetics, Microbiology and Immunology Suhayl Dhib-Jalbut, M.D., Professor of Neurology and Molecular Genetics, Microbiology and Immunology Edmund C. Lattime, Ph.D., Professor of Surgery and Molecular Genetics, Microbiology and Immunology Paola Leone, Ph.D., Associate Professor of Surgery and Molecular Genetics, Microbiology and Immunology
  15. 15. Joint Appointments, Cont'd Randall D. McKinnon, Ph.D., Associate Professor of Surgery and Molecular Genetics, Microbiology and Immunology M. Maral Mouradian, M.D., Professor of Neurology and Molecular Genetics, Microbiology and Immunology Daniel A. Notterman, M.D., Professor of Pediatrics and Molecular Genetics, Microbiology and Immunology Karel F. Raska, Jr., M.D., Ph.D., Clinical Professor of Pathology and Adjunct Professor of Molecular Genetics, Microbiology and Immunology Michael Reiss, M.D., Professor of Medicine and Molecular Genetics, Microbiology and Immunology Roger K. Strair, M.D., Ph.D., Associate Professor of Medicine and Adjunct Associate Professor of Molecular Genetics, Microbiology and Immunology Moti L. Tiku, M.D., MBBS, Associate Professor of Medicine and Adjunct Associate Professor of Molecular Genetics, Microbiology and Immunology Adjunct Faculty Chiann-Chyi Chen, Ph.D., Adjunct Assistant Professor Evelyn Erenrich, Ph.D., Adjunct Assistant Professor Stephane Gross, Ph.D., Adjunct Assistant Professor Mei-Ling Li, Ph.D., Adjunct Assistant Professor Srijata Sarkar, Ph.D., Adjunct Assistant Professor Lee Ann Schein, Ph.D., Adjunct Assistant Professor Volunteer Adjunct Faculty Sefik S.Alkan, Ph.D., Adjunct Professor Edward Arnold, Ph.D., Adjunct Professor David P. Beck, Ph.D., Adjunct Professor C. Thomas Caskey, M.D., Adjunct Professor Graham R. Cleaves, Ph.D., Adjunct Assistant Professor Dalia Cohen, Ph.D., Adjunct Associate Professor Jeffry Cook, Ph.D., Adjunct Assistant Professor Wendy D. Cornell, Ph.D., Adjunct Assistant Professor Lori R. Covey, Ph.D., Adjunct Associate Professor Gorbadhan Das, Ph.D., Adjunct Professor Jonathan D. Dinman, Ph.D., Adjunct Associate Professor Jürgen Drews, M.D., Adjunct Professor Arthur M. Felix, Ph.D., Adjunct Professor Robert C. Gallo, M.D., D.Sc., Adjunct Professor Gianni Garotta, Ph.D., Adjunct Professor Carlos I. Gonzalez, Ph.D., Adjunct Assistant Professor Alice B. Gottlieb, M.D., Ph.D., Adjunct Professor Christopher Janson, M.D., Adjunct Assistant Professor Florence C. Kimball, Ph.D., Adjunct Associate Professor King-Teh Lin, Ph. D., Adjunct Instructor George E. Mark III, Ph.D., Adjunct Professor
  16. 16. Volunteer Adjunct Faculty, cont'd Fred Mermelstein, Ph.D., Adjunct Assistant Professor Margaret Prescott, Ph.D., Adjunct Associate Professor Abbas Rashidbaigi, Ph.D., Adjunct Assistant Professor Karel Raska, M.D., Ph.D., Adjunct Professor Hugh Rosen, M.D., Ph.D., Adjunct Assistant Professor John J. Siekierka, Ph.D., Adjunct Assistant Professor Leonard H. Sigal, M.D., Adjunct Professor Michael Steinmetz, Ph.D., Adjunct Professor Peter Tolias, Ph.D., Adjunct Professor George B. Weiss, Ph.D., Adjunct Professor Lawrence P. Wennogle, Ph.D., Adjunct Assistant Professor Carol J. Wilusz, Ph.D., Adjunct Assistant Professor Junxia Xie, Ph.D., Adjunct Assistant Professor
  17. 17. Research Associates, Postdoctoral Appointees Full-time Laboratory Staff Xiangfeng Cui, Ph.D. Jyoti Das, M.S. Christopher Krause, Ph.D. Satish Devadas, Ph.D. Regina Felder-Gibbions Lara Izotova, Ph.D. Predoctoral Trainees Danny Tu Khounh Sandra Chesoni Scott Kinzy Jennifer Defren Xiangyang Li Lauren DeStefano Baisong Liao, Ph.D. Anthony Esposito Olga Mirochnitchenko, M.S. Frances Gratacos AnnMarie Pacchia, Ph.D Yvette Green Cheryl Rebsch Malavika Gupta Arthur Roberts Jennifer Hurley Barbara Schwartz, M.S. Patricia Irizarry-Barreto Xiao-Juan Xu Anna Knapinska Zengrong Yuan, Ph. D. Hui-Ling Rose Lee Liying Zhang, M.D.. Mohan Liu Sofiya Micheva-Viteva Sayandip Mukherjee Office Staff Sedide Ozturk Walter Barnes Bradley Phelan Jamie Carr Yvette Pittman Gabriel Dava Meredith Prysak Ellen Feibel Guangwen, Ren Andrea Finamore Rohini Roy Rosalie Reina Estelle Ruidiaz Shannon Smith Jared Sharp Antionette Thomas Kristina Sutphen Zhihong Yang Business Manager Yingyu Zhang Rick Wernoski, MPA Riza Ysla Part-time Laboratory Staff Octavia Gamble Yan Hu Xi Jiang, M.S. Sheila Mazar Beverly Novembre
  18. 18. DEPARTMENTAL ACTIVITIES Appointments Stephane Gross, Ph.D., Appointment as Adjunct Professor of Molecular Genetics, Microbiology and Immunology, effective 12/01/05 Students Receiving Ph.D. Degrees Pedro Ortiz, defended 1/20/2006 Departures/Transfers Antoniette Thomas, retired 8/31/2005 Rick Wernoski left, 6/1/2006
  19. 19. DEPARTMENTAL COMMITTEES Vice Chairman Victor Stollar Standing Advisory Committee Renovations Committee Jerome Langer Terri Goss Kinzy Michael Leibowitz Jerome Langer Victor Stollar Rick Wernoski Core Facility Committee MGMI Retreat Committee Terri Goss Kinzy Gary Brewer Lee Ann Schein Andrea Finamore Barbara Schwartz Victor Stollar Rick Wernoski Rick Wernoski Seminar Committee Equipment Committee Gary Brewer Donald Dubin Terri Goss Kinzy Terri Goss Kinzy Andrea Finamore Michael Leibowitz Rick Wernoski Barbara Schwartz Nancy Woychik Rick Wernoski Faculty Recruitment Committee Holowczak Memorial Committee Arnold Rabson Paul Copeland Yacov Ron Andrea Finamore Yufang Shi Victor Stollar Nancy Woychik Rick Wernoski
  20. 20. Activities of MGMI Faculty Members 2004-2005
  21. 21. Gary Brewer, Ph.D. Research Activities Dr. Brewer’s research involves the study of proto-oncogene and cytokine messenger RNA, specifically their stability and translation and their regulation. These mRNAs are controlled via A+U-rich elements (AREs) present in the 3’-untranslated regions of the mRNAs. AREs target the mRNAs for rapid degradation and/or translational repression. His main focus is on how the ARE-binding protein AUF1 recognizes its target RNA sequences and how its binding affects gene expression. He discovered previously that AUF1 exerts its actions via its association with other cytoplasmic proteins, including translation factors and heat shock proteins. Knockdown of AUF1 using RNA interference stabilizes the ARE-mRNAs examined, proving its role in ARE-mediated mRNA decay. Highlights of the Year He published two seminal papers regarding regulation of genes involved in genotoxic stress responses and in breast cancer. These papers identify the RNA-binding protein AUF1, which we discovered in 1991, as a critical regulator of the GADD45α (genotoxic stress) and c-Yes (kinase involved in breast cancer) genes. Publications Sommer, S., Cui, Y., Brewer, G., and S.A.W. Fuqua. 2005. The c-Yes 3’-UTR contains adenine/uridine-rich elements that bind AUF1 and HuR involved in mRNA decay in breast cancer cells. Steroid Biochem Mol Biol. 97:219-229. Lal, A., Abdelmohsen, K., Pullman, R., Kawai, T., Yang, X., Brewer, G., and Gorospe, M. 2006. Post-transcriptional derepression of GADD45α by genotoxic stress. Mol. Cell 22:117-128. Brewer, G. and Chesoni, S.A. 2006. hnRNP D. AfCS-Nature Molecule Pages, (doi:10.1038/mp.a003244.01). Knapinska, A.M., Irizarry-Barreto, P., Adusumalli, S., Androulakis, I., and Brewer, G. 2005. Molecular mechanisms regulating mRNA stability: Physiological and pathological significance. Curr. Genomics 6: 471-486. M. Gupta and Brewer, G. 2006. MicroRNAs: New players in an old game. Proc. Natl. Acad. Sci. USA 103: 3951-3952. Presentations “AUF1: Where nonsense-mediated meets ARE-mediated mRNA decay”. Delivered July 8, 2005 at the BBSRC USA-UK Workshop on Mechanism and Control of
  22. 22. Posttranscriptional Gene Expression, NY Academy of Sciences, New York, NY. “AUF1: Where nonsense-mediated meets ARE-mediated mRNA decay”. Delivered August 30, 2005 at the EMBO Workshop on Mechanisms of mRNA Decay, Arolla, Switzerland. “Posttranscriptional regulation within the transcriptome of human tissues”. Delivered May 10, 2006 at the DIMACS Workshop on Clustering Problems in Biological Networks, Rutgers University, Piscataway, NJ Teaching MGMB 6000, Microbiology & Immunology , 1 lecture hour MICR 9000, Research in Mol. Genetics, Virology, Cell Biol., Genetic Engineering Elective Contact Person 01:146:470+16:148:514, Advanced Cell Biology/Mol Biol of Cells , 6 lecture hours 01:146:470, Biointerfacial Characterizations, 1 laboratory hour MICMOLGEN 681:612, Lab Rotations, 60 laboratory hours Student mentor for three graduate rotation students BIOL 01:119:406, Research in Biology, 45 laboratory hours Mentor to four undergraduate students Honors Elsie Eggert/American Heart Association Research Fellow, 2003-2005. Graduate Student Committee Memberships Member, Preliminary Oral Examination for Rose Marie Caratozzolo (Gunderson), November 10, 2005 Member, Final Ph.D. Examination for Kristi Muldoon Jacobs (Dinman), May 1, 2006 Member, Preliminary Oral Examination for Kelvin Cuban (Copeland), June 14, 2006 Seminars Sponsored December 6, 2005; Philip Marsden, M.D.; University of Toronto, Dept of Medicine; "Post-transcriptional gene regulation in vascular endothelium: A tale of endothelin-1 and verotoxins (Shiga-like toxins)"
  23. 23. Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Rutgers Undergraduate Research in Biology/Genetics & Microbiology: Neha Das, Naznin Daginawala, Shannon Scabatto, Yoniara Rivera, Pamela Allahyari Douglass College Project SUPER students: Lauren Rose Maher, Breena Krieger, Aradia Herbst-Gervasoni, Jaquelyn Bradley Student Assistants: Swati Gupta, Alexandria Wierzbowski, Vickey Tsai, Yanan Zhou, Sri Adusumalli, Julianna Small RWJMS Summer Research Fellowship Program student: Tina Park Research Associate: Baisong Liao Graduate Students: Sandra Chesoni. Kristina Sutphen, Lili Banihashemi, Estelle Ruidiaz, Jennifer Defren, Anna Knapinska, Frances Gratacos, Malavika Gupta, Patricia Irizarry, Riza Ysla Graduate Rotation Students: Minnkyong Lee, Yanique Rattigan; Kaitlin Guzzi RISE summer students: Franchesca Fiorito, Chin-Ho Poon Administrative Committees Departmental
  24. 24. Member, Departmental Seminar Committee Member, Retreat Committee, Department of Molecular Genetics, Microbiology, & Immunology University Director, Tutoring Program for Graduate School of Biomedical Sciences (GSBS) Member, Student Affairs and Academic Standing Committee of Graduate Program in Molec. Genetics and Microbiology Federal/State Appointments Ad hoc reviewer: RITE Study Section for NIH, November 2, 2005; NIH Study Section on Genes, Genetics, Genomics (postdoc fellowships), March 2-3, 2006 and July 13- 14, 2006; BMCT Study Section for NIH, June 23, 2006;TRN-6 Study Section (predoc fellowships) for the DOD, June 28, 2006 Community Involvement on Behalf of University or Medical School Sponsor for Pamela Allahyari, Rutgers University, Research in Biology, Fall 2005 Sponsor for Neha Das, Rutgers University, Henry Rutgers Research in Biology, 2005- 2006 Sponsor for Naznin Daginawala, Rutgers University, Honors Research in Biology, 2005- 2006 Sponsor for Shannon Scabatto, Rutgers University, Research in Genetics, 2005-2006 Sponsor for Yonaira Rivera, Rutgers University, Honors Research in Biology, 2005- 2006 Sponsor for Franchesca Fiorito, University of Puerto Rico - Rio Piedras, RISE Program, Summer 2005 Sponsor for Chin-Ho Poon, University of Rochester, RISE Program, Summer 2006 Sponsor for Breena Krieger, Lauren Rose Maher, Aradia Herbst-Gervasoni, and Jaquelyn Bradley, Douglass College Project SUPER, Spring 2006
  25. 25. Paul R. Copeland, Ph.D. Research Activities Incorporation of selenocysteine Selenocysteine is a unique amino acid that is incorporated specifically into a select group of essential proteins. This process represents a modification of the standard protein synthetic machinery in that it requires the utilization of a novel translation elongation factor (eEFSec), a selenocysteine insertion sequence (SECIS) element in the 3' untranslated region (UTR) of selenoprotein mRNAs, and a novel SECIS binding protein termed SBP2. These factors act in concert to alter the coding potential of specific in-frame stop codons (UGA) by specifying the insertion of selenocysteine at that site. One of the goals of our work is to understand the interplay between SBP2 and the translation machinery. Since SBP2 is a limiting factor required for Sec incorporation, it is central to the regulation of synthesis of selenoprotein, many of which are known to play critical roles in cellular defense from oxidation. As a result, SBP2 will be a key target for methods designed to increase the beneficial properties of selenoproteins including the prevention of DNA damage in carcinogenesis and oxidation of pathogenic lipids involved in atherosclerosis. We seek to understand the detailed function of SBP2 by studying its specific interaction with ribosomes and its interaction with the machinery that would ordinarily dictate the termination of translation at selenocysteine (UGA) codons. Our preliminary studies indicate that SBP2 specifically interacts with ribosomal RNA from a variety of species, indicating that the SECIS element may have evolved from highly conserved rRNA structures. This study will focus on mammalian cells as well as the yeast S. cerevisiae in order to thoroughly explore this interaction while exploiting the unique benefits of each system. Specifically, we are using mammalian rRNA fragments to probe the binding characteristics of SBP2. This is being done in combination with an analysis of SBP2 binding to intact yeast ribosomes in vitro and in vivo. In addition, we will directly assess the role of SBP2 in preventing termination at selenocysteine codons by analyzing Sec incorporation from efficient and inefficient templates. The information we obtain about the function of SBP2 will be used to develop a detailed model for Sec incorporation that should shed light on the basic mechanism of translation termination as well as enable us to identify components of the system that can be manipulated in order to optimize selenoprotein synthesis. Selenium and Cancer In 1996, it was reported that dietary selenium supplementation resulted in a significant reduction in total cancer mortality and specifically reduced the incidence of lung, colorectal and prostate cancers (Clark et al., 1996). Increased dietary selenium is either acting through the increased production of selenoproteins or through the action of selenium-containing small molecules that have unknown function. Since many selenoproteins provide a protective barrier against oxidative damage to cellular components, including DNA, we believe that a significant part of the chemoprotective effect of selenium supplementation is the result of an increase in selenoprotein expression. If increased dietary selenium is primarily functioning through the
  26. 26. selenoprotein pathway, then prostate cancer cells are likely to have altered selenoprotein expression. Indeed, it has been observed that at least one selenoprotein is dramatically reduced in prostate cancer. It is therefore of great importance to determine whether selenoprotein synthesis is a central part of the protective action of selenium, and thus a study of the regulation of this process is a critical part of discovering the mechanism of selenium chemoprevention. Specifically, this study will assess the effects of both increased selenium and increased selenoprotein synthetic capacity on cadmium-induced carcinogenesis of normal prostate cells in culture. In addition, to address the regulation of selenoprotein synthesis during prostate oncogenesis, we will identify the point of regulation responsible for the dramatic down- regulation of selenoproteins in prostate cancer as well as determine the contribution of the selenocysteine incorporation machinery to this regulation. Within the context of selenoprotein synthesis, it is important to note that all of the required factors may not be known. One of the ultimate goals of this research is to identify means by which to modulate the efficiency of selenoprotein synthesis, ideally in a selenoprotein-specific manner. Toward this end we are studying the SBP2-like protein (SLP), which is preferentially expressed in human prostate. This protein has no known function, but is similar enough to SBP2 to strongly suggest that it is involved in selenocysteine incorporation. Our study will provide evidence for the contribution of SLP to selenocysteine incorporation in order to provide a foundation for future work that will dissect its apparently prostate-specific function. Highlights of the Year Kelvin Caban, a graduate student in the lab, has completed a saturation mutagenesis in the RNA binding domain of SBP2 and has obtained a number of very interesting mutants. We have mapped these mutations onto the structure of the conserved L7Ae RNA binding domain and found a clear indication that SBP2 makes at least two contacts with the ribosome (see image). The residues in white are required for SBP2 function and thus describe a new motif involved in Sec incorporation that is likely involved in ribosome modification. Publications Peer Reviewed Articles: Kinzy, S.A., Caban, K. and Copeland, P.R. (2005) Characterization of the SECIS binding protein 2 complex required for the co-translational insertion of
  27. 27. selenocysteine in mammals. Nucl Acid Res. 33:5172-5180. Caban, K. and Copeland, P.R. (2006) Size matters: a view of selenocysteine incorporation from the ribosome. Cell Mol. Life Sci. 63:73-81. Abstracts: Translational Control 2005. Heidelberg, Germany, “Characterization of the SBP2-dependent selenocysteine incorporation complex.” Caban, K., Kinzy, S.A., and Copeland, P.R. NJCCR Cancer Research Retreat, Piscataway, NJ May, 2006 Presentations FASEB Summer Conference on Trace Elements – invited speaker, Snomass, CO June, 2006 Urology Grand Rounds, RWJUH, New Brunswick, NJ January 2006 Teaching Biochemistry 501 Seminar Course Microbiology and Immunology MGMB-6000 – Antibiotics Lecture MICR 5684 RNA Protein Interactions Graduate Student Committee Memberships Pedro Ortiz (MGM doc) – thesis committee member Vasanti Subramanian (BIOC doc) – thesis committee member Kristina Sutphen (MGM doc) – thesis committee member Sandra Chesoni (MGM doc) – thesis committee member Lili Banihashemi (MGM doc) – thesis committee member Jennifer Hurley (MGM doc) – qual exam committee member Jennifer Defren (MGM doc) – qual exam committee member Yvette Green (MGM doc) - qual exam committee member Estelle Ruidiaz (MGM doc) – qual exam committee member Frances Gratacos (MGM doc) – qual exam committee member Malavika Gupta (MGM doc) – qual exam committee member Administrative Committees Elected member, Executive Council Member, Foundation Grant Review Committee Member, Graduate Initiatives Committee Departmental
  28. 28. Holowczak Memorial Committee Chairman, Department Website Committee RWJMS Research Day Committee Member, Molecular Biosciences Admissions Committee Member, Qualifying Exam Committee Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Kelvin Caban (MGMI Ph.D cand.) Ilyssa Bennet (Rutgers undergrad) Nicole Shea (MGMI Ph.D cand.) Shannon Smith (Rutgers undergrad) Jesse Donovan (MGMI Ph.D cand.) Scott Kinzy (RTS III) Neil Rodriguez (MGMI Ph.D cand.) Cheryl Rebsch (RTS V) Katie Wright (Rutgers undergrad) Ruchira Ranaweera (Rutgers undergrad) Editing/Consulting Reviewer for: NIH Special Emphasis Panel Study Section (Nutrition) – grant review Manuscript Review Genome Biology Mol. Cell Biol.
  29. 29. RNA Nucl. Acid. Res.
  30. 30. Joseph P. Dougherty, Ph.D. Research Activities Research in our laboratory focuses upon studying retroviral replication as well as the design and development of retroviral vectors for gene therapy and anti-HIV-1 drug discovery. A more detailed description of our most recent work follows. Forward Chemical Genomics to Query HIV-1 Latency and Replication. Latency. Highly active antiretroviral therapy (HAART) provides remarkable suppression of HIV-1 replication. However, HAART does not lead to complete viral clearance. A primary cause for the lack of viral eradication is a population of chronically infected cells not targeted by the antiretroviral therapy. Those cells form a latent reservoir perpetuating the viral infection. Small molecules with pharmacological properties that allow them to reach viral reservoirs and to activate latent HIV-1 proviruses could result in clearance of HIV-1 infection when supplemented with HAART. To initiate discovery of such molecules, a cell based system that models HIV-1 latency has been developed. It provides a safe, sensitive, and reliable assay that can be used for high throughput screening (HTS). We have applied the system to screen a chemical library containing 200,000 compounds aimed at discovery of novel scaffolds that antagonize HIV-1 latency. From a variety of hits three compounds were selected as leads for further mechanistic studies and chemical modifications. These compounds proved to reproducibly reactivate latent provirus from two different lymphocyte based clonal cell lines as monitored by the expression profile of the markers included in the latency model system, namely, secreted alkaline phosphatase (SEAP) and enhanced green fluorescence protein (eGFP). The consistent reactivation of viral genes as evidenced by the pattern of expression of the markers assayed correlated with an increase in the relative levels of total viral mRNA. All three compounds act in synergy with the histone deacetylase inhibitor valproic acid augmenting the levels of marker gene expression comparable with those achieved with TNF-α. Our preliminary data showed that the new chemical compounds reactivate the latent provirus through different mechanisms. Further studies have to be done in order to find the precise mechanisms of provirus activation, which may uncover unique mechanisms responsible for establishing and maintaining HIV-1 latency. This study is an example of efficient combination of HTS drug discovery with the forward chemical genomics. Replication. In response to attempts to quell its spread, HIV continues to evolve by generating new recombinant genotypes and developing drug resistance. The need for additional methods of control is highlighted by recent reports of strains resistant to entire classes of antiretroviral drugs which aggressively assault the body’s immune system, resulting in alarmingly rapid progression to AIDS. Our efforts have focused on a new form of high throughput assay, which unlike previous assays for antiviral compounds, reconstitutes as many aspects of the viral life cycle as possible. We sought to exploit the high incidence of recombination that occurs during reassociation of reverse transcriptase during synthesis of the provirus. To this end, we have engineered a marker which is conditionally null while in the viral producing cells, but activated after
  31. 31. being transduced into infected cells, resulting in a quantitative assay representing the entire viral life cycle in a single well. We have created the stable producer cell lines needed for the assay and now work on optimization of the assay in a 384-well format. This assay shows a high degree of reproducibility, is designed to be compatible with the robotics used in high throughput screening of chemical libraries, and has been tested for safety. Successful preliminary studies using known HAART drugs in a 384-well format demonstrate the potential for future discoveries. This assay holds promise not only for the potential discovery of new antiviral compounds, but should also expose previously unknown aspects of HIV-1 interaction with host proteins. Retroviral Recombination. The basic mechanism of retroviral reverse transcription has remained unchanged for more than twenty-five years. Every model depicts DNA synthesis as being continuous using a single RNA template. However, we have obtained data indicating that this is not the case. We propose that the leading strand switches from one RNA template to the other RNA template multiple times during each and every cycle of replication. To date, the most compelling evidence comes from our work examining HIV-1 recombination. The data suggest that proviral progeny of heterozygous virions produced by cells harboring two genetically distinct retroviruses are all recombinant. However, this was in sharp contrast to previously reported data from the gammaretrovirus murine leukemia virus (MLV). A significant difference in the recombination rates between HIV-1 and MLV was previously reported, with the former being 10 to 100 times more recombinogenic. It was possible that preferential copackaging of homodimers in the case of MLV led to underscoring of its rate of recombination. To reexamine the recombination rates for MLV, experiments were performed to control for non-random copackaging of viral RNA, and it was found that MLV and HIV-1 exhibit similar recombination rates. In addition, a similar experiment was carried out with HIV-2, and it was also found that crossovers occurred at asimilarly high rate. Our work suggests that the basic mechanism of retroviral reverse transcription should be modified to reflect that template switching occurs multiple times during minus-strand DNA synthesis. This also implies that retroviral genes are essentially unlinked, indicating that retroviral replication is genetically akin to orthomyxovirus reassortment with one difference being that the breakpoints are random for retroviruses while they are defined by the segmented genomes of orthomyxoviruses. If recombination always occurs during retrovirus replication, this would make the process of recombination a core component of the virus lifecycle. A Novel Regulated Gene Expression System Using HIV-2 Derived Vectors. During the examination of the crossover rate of HIV-2, it was found that the HIV-2 based vectors and packaging system yielded very effective levels of gene transduction. We decided to develop HIV-2 based self-inactivating (SIN) vectors. The idea behind SIN vectors is that by deleting a portion of U3 in the 3’LTR the promoter region is destroyed, therefore after reverse transcription the provirus produced will contain LTRs with inactivated promoters. This should ensure that vector mobilization or proto-oncogene
  32. 32. activation downstream of any proviral integration site does not occur. In order to prevent regeneration of fully intact LTR by recombination during transfection, we further developed the SIN vector by replacing the U3 of the 5’LTR with a heterologous cytomegalovirus (CMV) promoter. This not only guarantees the unlikelihood of regenerating an intact LTR, but also renders the SIN vector Tat-independent. The titers generated in different adherent and non-adherent cells by using the Tat-independent SIN vector was found to be comparable or better than when using the transducing vector containing intact LTRs. This shows great promise in using this system and vector for gene therapy purpose. Gene therapy is the delivery of the gene of interest into the host whereby the deficiency of certain protein leading to specific diseases will be alleviated or cured. A major concern of delivery of the gene has always been the safety of the delivery system. Therefore, a regulated system would be more desirable because certain proteins are toxic if expressed in excess. Aminoglycosides have long been used to combat prokaryotes by inhibiting translation of protein synthesis. However, at lower concentrations it has been found that some aminoglycosides can suppress premature stop codon thereby inducing readthrough to produce functional proteins in eukaryotes. Recently, other small molecules have been discovered which exhibit functions similar to these aminoglycosides but with decidedly less toxicity. One such molecule is in clinical phase II trails and has been shown to be very well tolerated by patients. We have decided to further develop the Tat-independent SIN vector by making it inducible. However, unlike all the other inducible systems regulating at the transcriptional level, we aim to use the mechanism of premature stop codon suppression to induce readthrough as the regulatory system at the translational level. We will first use genes such as firefly luciferase for quantitation and bioluminescence evaluation, and GFP for quick visual detection. Once this inducible system has been optimized then genes, like GDNF (glial cell derived neurotrophic factor), that has the ability to cure real diseases when delivered to specific tissues in the host will be used and delivered into animal models such as that of Parkinson’s Disease. This way the effectiveness of delivery and inducibility of the system to cure or alleviate diseases will be evaluated. Highlights of the Year Carried out a high throughput screen which has provided lead molecules that can be used to develop drugs to clear HIV-1 latent infection and that can be used as probes to study HIV-1 latency. Developed a very efficient and safe HIV-2 lentiviral vector system for gene transduction Discovered that the recombination rate of disparate retroviruses is very high suggesting
  33. 33. that all retroviruses including HIV are always subject to crossovers during each and every cycle of replication indicating that the basic model of retroviral reverse transcription should be modified Publications Micheva-Viteva, S., A.L. Pacchia, Y. Ron, S.W. Peltz, and J.P. Dougherty. Human immunodeficiency virus type 1 latency model for high-throughput screening. Antimicrobial Agents and Chemotherapy. 2005 Dec;49(12):5185-8. Duttagupta, R., B. Tian, C.J. Wilusz, D.T. Khounh, P. Soteropolous, M. Ouyang, J. P. Dougherty, and S.W. Peltz. Global analysis of Pub1p targets reveals a coordinate control of gene expression through modulation of binding and stability. Molecular & Cellular Biology. 2005 Jul;25(13):5499-513. Zhuang, J., S. Mukherjee, Y. Ron, and J.P. Dougherty. High rate of genetic recombination in murine leukemia virus: implications for influencing proviral ploidy. Journal of Virology. 2006, Manuscript in Press. Mukherjee, S., H.L. Lee, A.L. Pacchia, Y. Ron, and J.P. Dougherty. Self-inactivating HIV-2 vector for efficient gene transduction. Manuscript in preparation. A HIV-2-based self-inactivating vector for enhanced gene transduction. Manuscript Submitted. Teaching Microbiology & Immunology (Medical Students) - 01:680:544:545 Molecular Virology (Graduate Students) - 16:681:555 Graduate Student Committee Memberships Advisor for: Rose Lee Sofiya Micheva-Viteva Sayandip Mukherjee Bradley Phelan Jiangling Zhuang (received PhD) Committee member for: Natasha Telesford Laboratory Staff Md. Anwar Hossain Rose Lee
  34. 34. Florence LeRoy Sofiya Micheva-Viteva Sayandip Mukherjee Annmarie Pacchia Bradley Phelan Danny Tu Khounh Jiang Xi Jiangling Zhuang Administrative Committees Departmental Director of the Graduate program in Molecular Genetics, Microbiology & Immunology Director of HIV Culture Facility University Executive Committee for the Molecular Biosciences Program (UMDNJ/Rutgers Joint Graduate Program) Chair of Institutional Biosafety Committee Executive Committee for the Graduate School of Biological Sciences (UMDNJ) Editing/Consulting Reviewed manuscripts for the Journal of Virology, Virology, and the Journal of Virological Method
  35. 35. Donald T. Dubin, M.D. Research Activities Dr. Dubin has stopped active laboratory research. He continues to follow the current literature on molecular mechanisms of antibiotic resistance in staphylococci and pneumococci. Administrative Committees Departmental Core Facility Committee Student Affairs and Academic Standing Committee (Chairman). RWJMS Committee of Review.
  36. 36. Terri Goss Kinzy, Ph.D. Research Activities The goal of the work in the Kinzy laboratory is to understand the structural and functional basis of G-protein regulation and post-transcriptional mechanisms that regulate gene expression. The components of the Translation Elongation apparatus in yeast, from soluble protein factors to the ribosome, allow an integrated approach to these questions. These components are targets for antibiotics and antifungals, mutant forms and inappropriate expression of these proteins are found in several human carcinomas, one is a target for diphtheria and related toxins, and mutations in several components affect the accuracy and efficiency of protein synthesis and viral replication. We are applying complementary genetic, molecular, biochemical and structural techniques to dissect the mechanism of events occurring during protein synthesis, the physical and functional interaction of Elongations Factors (eEFs) with other factors that regulate gene expression, and the interaction between this G-protein and its GTPase activating factor (GAP), the ribosome. D aa eEF2 GTP OH aa-tRNA binding Translocation ATP A GTP C eEF3OH GTP aa OH E B GTP GDP E P A eEF1A GDP Peptidyl aa transfer Codon recognition GTP hydrolysis eEF1Bαγ Fig. 1: Translation elongation in S. cerevisiae, highlighting the role of eEF1A in aa-tRNA delivery (A), eEF2 in translocation (C), eEF3 in E-site function (A) and eEF1Bαγ in nucleotide exchange (E). The eEF1 protein complex is prototypical of all G-proteins, such as the oncogene Ras, and as such is regulated by a classic "GTPase" switch mechanism. The GTP- dependent activity of eEF1A is to deliver aminoacyl-tRNA to the ribosome and sense the accuracy of this process. The guanine nucleotide exchange factor (GEF) eEF1Balpha is essential in yeast and responsible for catalyzing the exchange of GDP for GTP to maintain the pool of active protein. Using a genetic system devoid of the eEF1Balpha protein allows us to manipulate eEF1A without its GEF to understand the regulation of G-protein activity and mutant forms of eEF1Balpha allow us to dissect the mechanism of guanine nucleotide exchange in vitro and the consequences of changes in this protein’s activity in vivo. Lastly, the eEF1Bgamma subunit affects the sensitivity of the cell to oxidative stress. Current work is addressing the implications of this finding in post-transcriptional control using a proteomics approach. The two other factors involved in elongation, eEF2 the translocase and eEF3, a fungal specific factor, are
  37. 37. integrated with above work to fully dissect the mechanisms of protein synthesis and to better understand their potential as drug targets. We have worked in collaboration with Dr. Gregers Andersen to perform X-ray crystallographic studies of the eEF1 subunits, eEF2 and eEF3. Highlights of the Year In the past year her understanding of the role of the translation elongation factor 1A (eEF1A) has extended beyond its canonical role in delivery of aminoacyl-tRNA for elongation. She have published novel mutants that separate the actin and translation functions of eEF1A, providing a new example of a multifunctional protein and a link between the translational apparatus and regulation of the actin cytoskeleton. Additionally, the regulation of the levels of eEF2, the translocase, and the novel effect of dominant negative mutants on the cell were determined. Publications Magazinnik, T., Anand, M., Sattlegger, E., Hinnebusch, A.G., and Kinzy, T.G (2005) Interplay between GCN2 and GCN4 expression, translation Elongation Factor 1 mutations, and translational fidelity in yeast. Nuc. Acids Res. 33: 4584-4592. Gross, S.R. and Kinzy, T.G. (2005) The translation elongation factor 1A plays essential regulatory functions in the organization of both the actin cytoskeleton and cell morphology Nature Struct. Mol. Bio. 12:772-778. COVER Ortiz, P.A. and Kinzy, T.G. (2005) Dominant Negative Mutant Phenotypes and the Regulation of Translation Elongation Factor 2 Levels in Yeast. Nuc. Acids Res 33:5740-5748. Chatterjee, I., Gross, S.R., Kinzy, T.G. and Chen, K.Y. (2006) Rapid depletion of mutant eukaryotic initiation factor 5A at restrictive temperature reveals connections to actin cytoskeleton and cell cycle progression. Mol. Gen. Genomics 275:264-276. Abstracts Nissen, P., Nilsson, J., Jørgensen, R., Andersen, C., Boesen, T., Andersen, G.R., Goldman, Y., Ortiz, P., Anand, M., Balar, B., Ulloque, R., Kinzy, T.G. , Structural and functional studies of the yeast ribosome and elongation factors, Human Frontier Science Program Meeting, Washington DC, 2005. (platform presentation) Kinzy, T.G., Pittman, Y.R., Ozturk, S., Patel, S., Jeppesen, M.G. and Andersen, G.R., Regulation of Translation Elongation via the Guanine Nucleotide Exchange Factor eEF1Bαγ, Mechanism and Control of Posttranscriptional Gene Expression: A UK-USA Workshop, New York, 2005. (platform presentation)
  38. 38. Pittman, Y., Valente, L., Jeppesen, M.G., Andersen, G.R., Patel, S. and Kinzy, T.G. Biochemical and Mutational Analysis of eukaryotic translation elongation guanine nucleotide exchange factor, eEF1B , Experimental Biology 2006. (platform presentation) Bockhorn, J., Balar, B., Copeland, P., Kinzy, T.G., Characterization of Selenium Metabolism in Saccharomyces cerevisiae: Implications in Anti-Oxidant Potential. The 2006 Annual Retreat on Cancer Research in New Jersey, Piscataway, NJ. Bockhorn, J., Balar, B., Copeland, P., Kinzy, T.G., Development of Selenomethionine Resistant Saccharomyces cerevisiae Strains for X-ray Crystallography. 2006 Aresty Undergraduate Research Symposium, Rutgers University, Piscataway, NJ. Presentation Johns Hopkins: Physical and functional interactions between the translational apparatus and the actin cytoskeleton in yeast. 5/9/2006 Teaching Medical Microbiology - UMDNJ RWJMS – 17 Laboratory Hours Intro. to Mol. Biol. and Biochemistry Research (RU 15:315) - Rutgers University – 1 Lecture Hour The Application of Fungal Systems to Mol. & Cell. Bio. MICR 5683 – UMDNJ-RWJMS/ GSBS – 2 Lecture Hours -- Co-Course director RNA protein interactions: Rutgers: 16:681:684RWJMS: MICR 5684 - UMDNJ RWJMS/ GSBS – 14 Lecture Hours -- Co-Course director Molecular Virology - UMDNJ RWJMS/GSBS – 15 Lecture Hours Summer clinical internship presentation “Use of fungal systems in drug target development” RISE presentation “The devil in the details: record-keeping and falsification of data” Honors R. Walter Schlesinger Basic Science Mentoring Award Recipient
  39. 39. Seminars Sponsored Christopher Hellen, SUNY Downstate, 2/14/06 Mechanisms of translation initiation by internal ribosomal entry Graduate Student Committee Memberships Thesis Committee Member: Sanaz Oghlidos (Rutgers CDB) Barbara Siminovich-Blok (RWJMS Biochem.) Radharani Duttagupta (RWJMS MGMI) Committee Member: Carmela Palmero (RWJMS Pharm) Mariela Reyes-Reyes (RWJMS Biochem) Tyra M. Hall-Pogar NJMS BMB) Sandra Chesoni (RWJMS MGMI) Barbara Siminovich-Blok (RWJMS Biochem.) Shin-Wu Liu (Rutgers CDB) Graduate Student Committee Memberships PhD Kristi L Muldoon Jacobs (RWJMS MGMI) Mariela Reyes-Reyes (RWJMS, Biochem) Carmela Palermo (RWJMS, Pharm) Bill Schneider (RWJMS, Biochem) Rutgers Undergraudates Jecssica Bockhorn Kathleen Wright PhD/MS committee member: Lizbeth Romero (RWJMS Biochem) Tyra M. Hall-Pogar (NJMS BMB) Shin-Wu Liu (Rutgers CDB) Kristina Sutphen (RWJMS MGMI) Jennifer Hurley (RWJMS MGMI) Johnny Ma (Rutgers MBB) Aníbal Soto (Rutgers MMG) Estelle M. Ruidiaz (RWJMS MGMI) Kelvin Caban (RWJMS MGMI) Danielle Macario (RWJMS BME)
  40. 40. Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Postdoctoral Appointees: Monika Anand Ph.D., Stephane Gross Ph.D. Doctoral Students: Pedro Ortiz, Yvette Green, Sedide Ozturk, Anthony Esposito Undergraduates: Jessica Bockhorn, Nidhi Sondhi, Natalie Colimon, Eden Seitomer, Peter Krueger Rotation Student: Connan Vasa Administrative Committees Department committees, task forces, projects MGMI Seminar Committee MGM Graduate Program Admissions Committee MGMI Core Facilities Committee MGMI Renovations Committee MGMI Equipment Committee Department of Medicine Grants Review School committees, task forces, projects UMDNJ RWJMS Director, UMDNJ RWJMS DNA Synthesis and Sequencing Laboratory Cancer Institute of New Jersey Scientific Council Research Committee Co-Chair, Core Facility Committee Co-organizer UMDNJ RWJMS/Rutgers Yeast Group NIEHS Center of Excellence Directors Internal Advisory Committee
  41. 41. RWJMS Master Educators Committee NIEHS Center of Excellence Pilot Grant Review Committee Foundation of UMDNJ RWJMS Grant Review Committee RWJMS Graduate initiatives committee RWJMS Year Long MD Student Research Fellowship Committee RWJMS HHMI Precollege Science Education Initiative for Biomedical Research Institutions Grant Committee University/Campus committees, task forces, projects UMDNJ Master Educator Guild UMDNJ Master Educator Guild Executive Committee Admissions activities RWJMS MD PhD Admissions Committee Recruitment activities RWJMS Reception for accepted medical students RWJMS Open House Community/state service Science outreach, Bridgewater-Raritan Middle School and Patrick McGowen School, Invited speaker Women in Science and Engineering Fashion Show for middle and high school girls. Executive Leadership in Academic Medicine (ELAM) Program for Women National Advisory Committee Executive Leadership in Academic Medicine (ELAM) Program for Women National Curriculum Committee Editing/Consulting Ad Hoc Reviewer: Nucleic Acids Research EMBO Journal EMBO Reports Journal of Biological Chemistry Genomics Genetics Molecular and Cellular Biology Biochemistry Protein Science European Journal of Biochemistry Molecular and General Genetics PLOS Cell Metabolism Service On Grant Review Panels, Study Sections, Committees: Reviewer, Wellcome Trust, U.K., International Science Foundation Member, N.I.H. Molecular Genetics C Study Section 2003-2007 National Science Foundation Biochemistry of Gene Expression Panel
  42. 42. Jerome Langer, Ph.D. Research Acitivities Dr. Langer continues work funded by the Alliance for Lupus Research directed at the design of inhibitors of Type I interferon that might be useful in the treatment of lupus (systemic lupus erythematosus). His laboratory is designing mutants of human interferon alpha that we hope will be competitive antagonists of natural interferon; i.e., they will bind to the receptor, will not trigger biological responses, and will block the activity of endogenous interferon. The project is a collaboration with Dr. Elizabeth Raveche (Dept. of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School). We have used mutagenesis to examine in detail one area of the surface of alpha interferon which has been implicated in receptor binding. Surprisingly, in the interferon subtype that they are examining, this area may not play a major role in receptor binding, despite evidence that it plays an important role in another interferon subtype. They are shifting our attention to other parts of interferon. Highlights of the Year Alpha interferon appears to be inappropriately, perhaps continually, produced in people with systemic lupus erythematosus (“lupus”), and this aberrant production of IFN likely contributes to the pathogenesis of this disease. To block the effects of IFN in lupus patients, we are attempting to design and produce modified IFNs that act as competitive antagonists of endogenous IFN. Dr. Langer has investigated several parts of the IFN molecule for their importance in interactions with the 2 subunits of the IFN receptor. He demonstrated that a region of IFN previously reported to be important in one IFN subtype for receptor interactions does not make strong contributions to receptor interactions in the IFN subtype used in our lab. His laboratory therefore proposed a novel model of IFN/receptor interactions, and is examining the effects of mutations in other parts of the IFN molecule. Publications and Presentations May 24-24, 2006. “Type I Interferon Antagonists for Lupus and Autoimmunity”. Alliance for Lupus Research Collaborative Meeting, New York, NY. Nov. 14, 2005. “Graduate Education Opportunities in the Sciences on the New Brunswick/Piscataway Campuses of UMDNJ and Rutgers”. University of Maryland, Baltimore County (UMBC), Meyerhoff Program.
  43. 43. Teaching Microbiology & Immunology (RWJMS) (Spring 2006) Laboratory instructor. Molecular Virology, Lecturer (Spring 2006) Research/Technical Writing Seminar, “Research in Science & Engineering (“RISE”) at Rutgers/UMDNJ” summer undergraduate research program, Co-director and seminar leader (Summer 2005) Seminars Sponsored 5/9/06 Christine Biron, Brown University, "Regulation of Innate Cytokine Induction & Function During Viral Infection" Graduate Student Committee Memberships Eddie Perez. Ph.D. thesis committee. Dept. of Biochem (Ann Stock, advisor). Member. Xuelie (Julie) Song. Ph.D. thesis committee. Dept. of MGMI (Bill Moyle, advisor). Member. Thesis defense: 9/8/05. Jiaying (Joyce) Huang, Ph.D. thesis committee, Dept. of Biochem. & Molec. Biol., New Jersey Med. Sch. (Sergei Kotenko, advisor). Member. Sedide Ozturk, Ph.D. thesis committee Dept. of MGMI (Terri Kinzy, advisor). Member. Megha Gandhi, M.S. thesis committee. Dept of Food Science, Cook College, Rutgers. (Mikhail Tchikindas, advisor). Member. Thesis defense: 9/21/05. Stephanie Williams, M.S. Thesis committee. Dept. of Physiology & Biophysics, RWJMS. (Nicola Partridge, advisor). Member. Thesis defense: 10/21/05. Distinction in Research M.D. students (RWJMS): Matthew Wosnitzer, Jennifer Tan (Faculty liaison; final committee). . Administrative Committees Departmental MGMI Academic Standing Committee, Member MGMI Committee on Review, Member RWJMS and GSBS RWJMS Distinction in Research Committee: member RWJMS Committee on Research Integrity, member RWJMS Community Service Strategic Planning Committee, Member RWJMS Review of Foundation of UMDNJ Grant applications, Member Molecular Biosciences Graduate Programs, Student Academic Standing Committee,
  44. 44. Member. Molecular Biosciences Graduate Programs, Rotation advisory committee, Member Molecular Biosciences Graduate Programs, Minority Admissions Subcommittee, Member. AAUP RWJMS Chapter, Executive Committee University AAUP Council of Chapters (UMDNJ). Treasurer. Editing/Consulting Journal of Interferon & Cytokine Research, Editorial Board. Ad hoc reviewer: “Biochemistry”; “Proteins: Structure, Function and Bioinformatics”; “Journal of Molecular Biology”; “Journal of Interferon & Cytokine Research” Laboratory Staff Manjing Pan, Ph.D., Post-doctoral Fellow
  45. 45. Michael J. Leibowtiz, M.D., Ph.D. Research Activities Beta-sheet blockers as therapeutic agents In collaboration with Dr. Stanley Stein, Dr. Leibowitz has shown that peptidomimetic agents structurally related to the nucleation site of human A-beta(1-42) amyloid monomer peptide can specifically bind to the monomer and prevent the formation of amyloid in vitro. With Dr. William Welsh he plans to use these and other agents interacting with various amyloids to determine if they can develop bioinformatic approaches to predicting agents binding to proteins that are capable of forming amyloids, such agents might be useful to stain amyloids or to inhibit or reverse their formation. This would have potential application to the diagnosis and treatment of human amyloid diseases. Polymeric Bioconjugates for Drug Delivery In collaboration with Drs. Stanley Stein and Patrick Sinko (Rutgers University), the Leibowitz lab is studying the use of polymeric bioconjugate drug delivery methods to improve the bioefficacy of treatment of AIDS and cancer. The basis for much of this work is the use of conjugates in which various drugs are linked to polyethylene glycol (PEG), resulting in reduced hydrolysis and renal clearance of the drugs and increased half-life. In addition, PEG conjugates decorated with multimeric effector molecules including cell targeting agents, membrane penetration agents and drugs are being developed. Multiple ligands for one or multiple cell surface receptors are being tested as means to deliver these conjugates to specific cells. They have shown that multiple copies of the chemoattractant peptide fMLF result in targeting of macrophages; experiments are planned to determine if the macrophage-specific mannose ligand shows similar effects of multiple copies on a single conjugate, and whether the two ligands might show synergistic targeting effects. These methods are being pursued to develop new therapies for infectious agents which attack macrophages, such as HIV-1 and Mycobacterium tuberculosis. Highlights of the Year Drug-carrying bioconjugates based on polyethylene glycol can be synthesized with attached ligands for cell surface receptors to target the conjugates to cells bearing those receptors, to which the drugs can then be delivered with great specificity. The laboratory has shown that multiple copies of formyl-methionyl-leucyl-phenylalanine attached to the bioconjugates can greatly enhance their delivery to macrophages. This has great potential for developing drug delivery systems for these cells, which are the primary infected cell type in AIDS and tuberculosis. Publications
  46. 46. Wan, L., Zhang, X., Gunaseelan, S., Pooyan, S., Debrah, O., Leibowitz, M.J., Rabson, Arnold B., Stein, S., Sinko, P.J. Novel multi-component nanopharmaceuticals derived from poly(ethylene) glycol, retro-inverso-Tat nonapeptide and saquinavir demonstrate combined anti-HIV effects. AIDS Research & Therapy, 3:12. (2006). M. Palombo, L. Wan, S. Pooyan, X. Zhang, S. Stein, M. Leibowitz and P.J. Sinko, Increasing Avidity Improves Peg-fMLF (N-Formyl-Methionine-Leucine- Phenylalanine) Nanocarrier Uptake by Macrophages, PharmSci supplement, M1123, (2006). S. Pooyan, L. Wan, P. Hu, X. Zhang, S. Stein, M. Leibowitz and P.J. Sinko, Peritoneal Macrophage Uptake, Pharmacokinetics and Biodistribution of Macrophage- Targeted Peg-fMLF (N-Formyl-Methionyl-Leucyl-Phenylalanine) Nanocarriers, PharmSci supplement, (2006). Presentations September 15, 2005, invited presenter at New Student Orientation, Office for Diversity and Academic Success (ODASIS), Rutgers University. August 24, 2005, speaker, Molecular Biosciences Graduate Programs Orientation. September, 28, 2005, speaker, Neuroscience Graduate Program Orientation. November 1, 2005, recruitment talks at Morehouse College and Spelman College, Atlanta, GA. February 22, 2006, invited speaker at University of Puerto Rico, Medical Sciences Campus, San Juan, PR, “Multiplex Bioconjugates Mediating Drug Delivery to Macrophages.” March 10, 2006, invited speaker at Duke University, “[KIL-d]: A Transfectable Prion-Like Virus Control Element.” June 28, 2006, “Choosing and Applying to Graduate School,” RISE (Research in Science and Engineering) at Rutgers/UMDNJ summer undergraduate research program.
  47. 47. Meetings Attended November 2-5, 2005, represented UMDNJ–GSBS and RWJMS at the Annual Biomedical Research Conference for Minority Students (ABRCMS), Atlanta, GA. November 29, 2005, invited speaker on “The Graduate School of Biomedical Sciences,” New Faculty Orientation, UMDNJ-RWJMS. February 16, 2006, NEA (Northeast Alliance) Day, University of Puerto Rico, Mayagüez, PR, sponsored by the NSF. February 21, 2006, URGREAT-MBRS-RISE Project External Advisory Board Meeting, Universidad del Este, Carolina, PR February 22-24, invited consultant, SCORE project (NIH-supported), University of Puerto Rico, Medical Sciences Campus. Teaching Microbiology and Immunology for Medical and Graduate Students; 16:680:544 (MICR 6000). Biomedical Engineering; Senior Design II, 14:125:402, Rutgers University School of Engineering; Lecturer Spring 2004. Ethical Conduct of Research; GSBS/RU DST-5000/16:115:556. RISE (Research in Science and Engineering) Program and Summer Neuroscience Research Program, Lecturer. Student Advisor for Rutgers College course Biomedical Issues of AIDS ( 01:119:152), Fall 2005 Honors Dennis J. Thiele (former graduate student) was awarded 2006 Distinguished Alumnus Award by Graduate School-New Brunswick, Rutgers University Graduate Student Committee Memberships Li Wan (Pharmaceutical Sciences, Rutgers University), Proposal Examination October 17, 2005. Ramón Scharbaai Vazquez (University of Puerto Rico, Medical Science Campus, San Juan), Ph.D. Thesis Defense May 17, 2006. Research Staff: Xiangyang Li, Research Specialist Andrei Nesterov, Student Assistant Ralitza Varlakova, Student Assistant Odette Williams, Student Assistant Undergraduate Students Supervised:
  48. 48. Odette Williams, Livingston College. Ralitza Varlakova, Rutgers College. Andrei Nesterov, Rutgers College. Christina Hansen, Research in Science and Engineering (RISE) at Rutgers/UMDNJ summer undergraduate research program Administrative Committees Departmental - MGMI Equipment Committee Executive Committee Admissions Committee RWJMS Executive Council, non-voting member Chair, Graduate Education Committee (same as Executive Council, UMDNJ-GSBS) Ad hoc member, Graduate Initiatives Committee, UMDNJ-RWJMS University Associate Dean, UMDNJ-Graduate School of Biomedical Sciences, Piscataway Chair, Executive Council, GSBS/Piscataway Director, Core Curriculum in Molecular and Cell Biology, UMDNJ-Rutgers University Steering Committee, M.D./Ph.D. Program, UMDNJ-RWJMS Executive Committee, Rutgers University/UMDNJ Consolidated Programs in the Molecular Biosciences Director, UMDNJ-Rutgers University Pipeline Program, NIH Initiative for Maximizing Student Diversity Award Director, UMDNJ-University of Puerto Rico (Mayagüez Campus) Bridge to the Doctoral Degree Program (NIH funded) Director, UMDNJ Component, Montclair State University-UMDNJ Bridge to the Doctoral Degree Program (NIH funded) Director, Internal Bridge Program, Articulated M.S./Ph.D. Program Member, Cancer Institute of New Jersey and Scientific Advisory Council and Internal Advisory Council of CINJ Admissions Committee, Biotechnology Training Program (joint with Rutgers, NIH) Breast Cancer Research Program, CINJ Graduate Research And Education Training (GREAT) Group, AAMC, UMDNJ-RWJMS Representative Co-Director, Molecular BioSciences Graduate Programs, Rutgers University and UMDNJ-GSBS UMDNJ Representative, Northeast Alliance for Graduate Education and the Professoriate, (NSF funded) Member, Council of Graduate Schools Member, Society for the Advancement of Chicanos and Native Americans in Science
  49. 49. Member, Piscataway Campus Summer Program Directors Member, Advisory Committee for the UMDNJ Presidential Search. (July, 2004) Member, MBRS and Bridges Program Directors Organizations Member, Academic/Education Deans Working Group, UMDNJ Ad hoc member, Diversity Subcommittee, Admissions Committee, Molecular BioSciences Graduate Programs, Rutgers/UMDNJ Member, UMDNJ Intellectual Property Committee Editing/Consulting Consultant, SCORE Program (NIH-supported), Medical Sciences Campus, University of Puerto Rico, San Juan, PR External Advisory Board, URGREAT-MBRS-RISE Project (NIH-funded), Universidad del Este, Carolina, PR Consultant, HIKMA Pharmaceuticals Reviewer for: Biochemistry
  50. 50. Honghua Li, Ph.D. Research Activities Research Activities Our laboratory is interested in understanding the molecular mechanisms affecting human health in a comprehensive way. We have been continuously targeting at biological systems that may have a major and comprehensive impact on human health and have been looking at the life process from different angles. Extending the Application of Our High-throughput Genotyping System. Realizing that understanding the biological systems in a comprehensive way requires high- throughput approaches, we have devoted much effort to establish a high-throughput genotyping system for nucleic acid detection and have been very successful. With this system, >1000 SNPs can be analyzed in a single assay, with a sensitivity allowing the use of single haploid cells as starting material. We first applied this system to the analysis of Single Nucleotide Polymorphisms (SNPs) on a large scale. During the past two years, we have also used it for gene expression profiling with high sensitivity and specificity and have been also very successful. More importantly, we have shown that the high-throughput system can be used to study gene expression in a quantitative way. A number of bioinformatic tools have been developed for analyzing data from the high- throughput assays. Understanding the Genetic Structure of the Human Genome. Meiotic recombination in humans has received considerable attention recently because of its importantce for understanding the genetic structures of the human genome and human evolution. Meiotic recombination is also likely to be one of the primary mechanisms for the formation of haplotype blocks, which is important for mapping genes responsible for complex diseases. However, very little is known about the details of meiotic recombination and the underlying mechanisms. Recent advances in developing new techniques have allowed major progress in revealing the meiotic recombination process. However, study of this process still largely remains descriptive. Our success with developing the high-throughput multiplex genotyping system has enabled us to determine the genotypes of single sperm cells at a large number of genetic loci. This makes is possible to studyg a chromosomal region in a great detail and to reveal the sites of meiotic recombination along the length of chromosomes. Recent findings have allowed us to better understand the correlation between meiotic recombination and haplotype block formation and thus to understand the mechanisms underlying genetic recombination in a comprehensive way. We have shown a strong correlation between meiotic crossovers and haplotype structure in a 2.5-Mb region on the long arm of chromosome 21. To investigate the role of meiotic recombination on haplotype block formation, SNPs were selected at a high density from a 2.5-Mb region of human chromosome 21. Direct analysis of meiotic recombination by high-throughput multiplex genotyping of 662 single sperm identified 41
  51. 51. recombinants. The crossovers were nonrandomly distributed within 16 small areas. All, except one, of these crossovers fall in areas where the haplotype structure exhibits breakdown, displaying a strong statistically positive association between crossovers and haplotype block breaks. The data also indicate a particular clustered distribution of recombination hotspots within the region. This finding supports the hypothesis that meiotic recombination makes a primary contribution to haplotype block formation in the human genome. Understanding the Genetic Basis of Breast Cancer on a Genomic Scale. Breast cancer is present as a spectrum of neoplasm. Clinically, various forms of proliferative lesions and malignancy have been observed. Although extensive histological and cytological studies have been reported, the molecular mechanisms underlying the high degree of heterogeneity of breast cancer remain poorly understood. It is widely believed that breast cancer development is a multi-step process caused by genetic alterations in a number of tumor suppressor genes and protooncogenes. We hypothesize that the high degree of heterogeneity of breast cancer is a reflection of involvement of different molecular pathways. On the other hand, difference in morphology may reflect the activity of distinct molecular pathways and may be used for understanding the genetic basis of breast cancer. To test the above hypothesis, we take the advantage of the fact that loss of heterozygosity (LOH) is usually associated with cancer development and has been shown to be an indication of tumor suppressor inactivation or protooncogene amplification. In most cases, LOH affects relatively large chromosomal regions containing the affected genes. Therefore, LOH can be detected by using genetic markers in these regions, even though these markers may not be necessarily located within the affected genes many of which are unknown. By examining LOH, the correlation between the responsive genes and the corresponding proliferative lesions and malignancy may be studied even without knowing the genes and their protein products. Currently, we have showed that >1,000 SNPs in a single diploid cell can be detected robustly by a single assay and that a few hundred cells microdissected from breast tumor tissue sections can be used for LOH analysis. These kinds fo findings will allow us to understand the molecular pathways underlying breast cancer development in a comprehensive way. It is expected that genome-scale analysis of the breast cancer lesions and malignancy will generate a tremendous amount of information that has not been available before. Highlights of the Year During the academic year of 2004-2005, we have made significant progress toward accomplishing our research goals. We have further extended the application of our high-throughput nucleic acid detection system. This system has been used for studying meiotic recombination in much more detail and on a large scale. We have also used it for studying genetic variation in breast cancer tissues and cell lines, and in colon cancer. We have been very successful in using this marker system, for the first time, to detect sites of meiotic recombination along entire chromosomes and to locate meiotic crossover points which then will improve the understanding of the mechanisms

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