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  2. 2. COMMUNICATION WITH PROGRAM We have received your letter expressing interest in the fellowship program at Children’s Hospital Boston. Enclosed is a brief summary of our current activities. We strongly recommend that you come for an interview. Most applicants have found that this interview is extremely helpful in clarifying our training program and our clinical and research facilities. We will be happy to discuss all aspects of the training program with you. Please feel free to contact us at: Office: (617) 355-6129 Fax: (617) 232-4315 David M. Briscoe, M.D. Co-Director, Training Program in Pediatric Nephrology Associate Professor of Pediatrics Harvard Medical School E-mail: David.Briscoe@childrens.harvard.edu
  3. 3. CURRENT STAFF AND FELLOWS STAFF William E. Harmon, M.D. Jordan Kreidberg, M.D., Ph.D. Chief, Division of Nephrology Assistant in Medicine John T. Herrin, MBBS, FRACP Nader Najafian, M.D. Director, Dialysis Unit Assistant in Medicine Mohamed Sayegh, M.D. Thomas Natoli, Ph.D. Director of Research Assistant in Medicine Michael J.G. Somers, M.D. Soumitro Pal, Ph.D. Director, Clinical Services Assistant in Medicine Michelle A. Baum, M.D, Elahna Paul, M.D., Ph.D. Assistant in Medicine Assistant in Medicine David M. Briscoe, M.D. Nancy M. Rodig, M.D. Associate in Medicine Assistant in Medicine Markus Frank, M.D. Asher Schachter, M.D. Assistant in Medicine Assistant in Medicine Indira Guleria, Ph.D. Assistant in Medicine FELLOWS Reza Abdi, M.D. Stefan Kiessling, M.D. Steven Arora, M.D. Armen Margaryan, M.D Gwenola Boulday, Ph.D. Stuart Robertson, M.D. Nibedita Chattopadhyay, Ph.D. Sigrid Sandner, M.D. Xing Chen, M.D. Charlie Szekeres, Ph.D. Michael Clarkson, M.D. Avram Traum, M.D. Jesse Flaxenburg, M.D. Cynthia Wong, M.D. Xiaobo Gao, Ph.D. Bing Zhu, M.D., Ph.D. Zdenka Haskova, M.D., Ph.D. Brian Hershenfield, M.D. Jamie Imitola, M.D. Atsushi Izawa, M.D. Reshma Kewalramani, M.D. Mona Khurana, M.D.
  4. 4. DESCRIPTION OF TRAINING PROGRAM The Nephrology Division at Children’s Hospital Boston is currently the largest Pediatric Nephrology division in the Untied States. One of the central goals of the Division is to develop academic Pediatric Nephrologists who will be able to establish independent investigative careers in areas relevant to the understanding of childhood Nephrology diseases. The Fellowship Program provides broad training in all the major areas of Nephrology with opportunities to develop clinical and research skills. There are three years of training composed of one clinical year and two years of laboratory research. The Training Program meets the requirements for certification by the Sub-board of Nephrology of the American Board of Pediatrics. The clinical training year provides the Fellow with extensive exposure to a wide variety of clinical problems in Pediatric Nephrology accomplished by full participation of fellows in all the patient care activities within the Division. This includes the direct care of Nephrology inpatients, serving as consultant to both inpatient and outpatient divisional programs; as well as the care of the transplant and pediatric dialysis outpatients and the general Nephrology clinic outpatients. Fellows become proficient in all of the technical aspects of Nephrology such as performing renal biopsies, hemodialysis and peritoneal dialysis. In addition, the Fellows acquire experience through the Department of Pathology in the interpretation of light, immunofluorescence and electron microscopy, and through the Department of Radiology in the interpretation of uroradiologic studies. The Division has two clinical services: the End-Stage Renal Disease Service (dialysis and transplantation); and the General Renal Consult Service. Each Fellow spends approximately equivalent time on the End-Stage Disease and the Consult Service. The fellow is responsible for: 1) supervising the care of all inpatients who are followed by the Division of Nephrology; 2) providing consultant services for Children’s Hospital Boston and the neonatal intensive care unit at the Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, and other affiliated community hospitals; and 3) performing acute dialysis and hemofiltration as well as all percutaneous renal biopsies. The two research fellowship years are a most important aspect of the Fellowship Training Program and are aimed at broadening the Fellow’s understanding of renal disease. One of the unique aspects of our training program is the ability to participate in one of the many ongoing research efforts in the Nephrology Research Laboratories. The Director of our Nephrology Research Program, Dr. Mohamed Sayegh and Dr. David Briscoe advise Fellows in the selection of a basic science research project approximately six months prior to initiating the laboratory research fellowship years. Our laboratory research faculty share a common interest and expertise in cellular and molecular biology, immunology, renal development, glomerular disease and transplantation biology. Research on the cell biology and transport mechanisms present in epithelia of the kidney, lung, and cell of the
  5. 5. central nervous system are also interests within the faculty. We have a Transplant Immunology Research Program, focusing on mechanisms of alloimmunity, functional interactions between lymphocytes and endothelial cells as well as immunologic tolerance. In addition, our renal development research program has a focused interest in the molecular regulation of organogenesis. We are expanding our program in glomerular disease, which currently is focused on the pathophysiolology of glomerulosclerosis. Also, a specific interest of the clinical research faculty is the pathophysiology of chronic Nephrology disease in children. Ongoing studies address growth abnormalities and defining risk factors influencing outcome of children undergoing chronic dialysis and transplantation therapies. In general, the schedule is designed to promote optimal exposure to all aspects of Pediatric Nephrology during the training years. First year Fellows are expected to prepare and present clinical conferences each month. In addition, Fellows actively participate in medical student teaching and house officer conferences. In subsequent years, the Fellow participates in the research conferences and makes periodic presentations of his/her research efforts at individual laboratory as well as divisional research laboratory seminars and journal clubs. Fellows also actively participate in medical student teaching and house officer conferences. Lastly, all research fellows are encouraged to attend Harvard seminars specific to their research interest including the Harvard Medical School Seminars in Immunology and Vascular Biology. Since very few pediatric Nephrologists can operate separately from an academic institution or large affiliated medical center, our experience has demonstrated that all of these aspects of our training program are designed to develop skills as a clinical scientist and teacher. We strongly believe that our training program provides the opportunity to develop interests in all aspects of the clinical science of Pediatric Nephrology.
  6. 6. CLINICAL YEAR SCHEDULE SERVICE TOTAL MONTHS End-Stage 6.0 Consult 5.5 Vacation 0.5 WEEKLY SCHEDULE A. End-Stage Service: Transplant/Dialysis 1. Inpatient rounds and outpatient dialysis rounds: daily 2. Transplant clinic: twice weekly 3. Dialysis Conference: weekly 4. Pre-transplant conference clinic: weekly 5. Post-transplant conference clinic: weekly 6. General Renal clinic: weekly 7. Division research conference: weekly 8. Clinical conference: weekly B. Consult Service 1. Inpatient rounds: daily 2. Consults 3. General Renal clinic: weekly 4. Transplant clinic: weekly 5. Division research conference: weekly 6. Clinical conference: weekly 7. Firm Rounds CALL SCHEDULE A. First Year: every third week B. Second Year: every sixth week C. Third Year: no call LICENSING Massachusetts license Annual Number of procedures performed in the Division are as follows: RENAL BIOPSIES 110 OUTPATIENT VISITS 3100 INPATIENT CONSULTS (plus Nephrology patients) 700 RENAL TRANSPLANTS 15-20 ACUTE PERITONEAL DIALYSIS TREATMENTS 10-20 ACUTE HEMODIALYSIS TREATMENTS 500 HEMOFILTRATION PATIENT-DAY 100 CHRONIC HEMODIALYSIS TREATMENTS 2500-3000 CAPD-CCPD PATIENT-MONTHS 50-100
  7. 7. HISTORY OF FELLOWSHIP TRAINING AT CHILDREN’S The central goal of the Pediatric Nephrology Fellowhip Training Program at Children’s Hospital Boston has been to develop full-time academic Pediatric Nephrologists who establish independent investigative careers in areas relevant to the understanding of childhood Nephrology diseases. Our training program has expanded over the last 10 years and currently has two components. The first component is the training of academic pediatricians in the specialty of Pediatric Nephrology, including investigative biology and the basic science pertaining to the pathophysiology of pediatric kidney disease. The second component of our program is to train scientists in the specialty of Pediatric Nephrology. Trainees who enter our program are exposed to a wide variety of individuals all dedicated to investigative Nephrology. These individuals have backgrounds in many different specialties and include students, pre-doctoral and postdoctoral candidates as well as PhD's. Our program ensures that all trainees work side by side which enhances their mutual education and creates an environment for rigorous scientific investigation. Thus, our program is currently established for the training of Pediatric Nephrologists and for the advancement of biomedical research in the specialty of Pediatric Nephrology. Since its inception in 1974, our program has graduated a total of 50 fellows from the Pediatric Nephrology fellowship program and is currently engaged in the training of another 6. In addition, we are currently training another 18 post-doctoral research fellows. Pediatric Nephrology trainees who graduate from our Program fulfill the criteria for certification in Pediatric Nephrology by the American Board of Pediatrics and the specialty sections of the American Academy of Pediatrics. Graduates of our program include 2 Department Chairmen, 8 Directors of Pediatric Subspecialty Divisions and 11 Directors of major research laboratories. In total we have trained at least 20 independently funded, established biomedical investigators since the inception of the program and most of our trainees are full-time faculty at academic pediatric hospitals or universities. At the national level, many of our trainees have received awards for their work. For instance, of nine trainees who completed our program in 2002-03, six received awards related to their research studies. Over the past 5 years, many of our trainees received notable awards, including: two NIH National Research Service Awards and one Pediatric Scientist Development Award. Also, several of our trainees who completed training within the past five years have received NIH career development awards including three K08s, one K01 and one K23. Graduates of our program are also identified as international leaders in nephrology research. For instance, several (E. Avner M.D., A. Arnaout M.D. and T. Kon M.D.) have been members of NIH study sections, three (A. Krensky M.D., D.M. Briscoe, M.D. and W.E. Harmon, M.D.) are recognized leaders in the field of kidney transplantation; one (L. Guay-Woodford, M.D.) is a leader in the field of inherited renal diseases; and one (S. Goldstein,
  8. 8. M.D.) is increasingly recognized as a major national authority in pediatric hemodialysis.
  9. 9. CURRENT FUNDED RESEARCH STUDIES WITHIN THE DIVISION 1. Mechanisms of Indirect Allorecognition and T Cell Co-stimulation in Acute and Chronic Rejection in Experimental Animal Models 2. Autoimmune Responses in Primates 3. Immunorecognition in Chronic Allograft Rejection 4. Calcineurin Inhibitor Sparing Protocol in Living Donor Pediatric Kidney Transplantation 5. Nuclear Factor Kappa B in Pediatric Nephrotic Syndrome 6. Mechanisms of Chronic Rejection in Humans 7. The Role of T Cell Co-stimulation in Tolerance Induction in Transplant Rejection and Autoimmunity 8. The Graft Vascular Endothelium in Chronic Rejection 9. Vascular Endothelial Growth Factor in Alloimmunity 10.Mechanisms of Islet Allograft Rejection and Tolerance 11.Angiogenesis and Chronic Rejection 12.The Effects of Sirolimus vs. Standard Treatment on Clinical Outcomes 13.Vascular Endothelial Growth Factor and Semaphorins in Kidney Development 14.Vascular Endothelial Growth Factor and Renal Inflammation 15.Use of Rituxan in Pediatric Solid Organ Recipients with Post-Transplant Lymphoproliferative Disorders 16.Vascular Endothelial Growth Factor in Acute and Chronic Rejection 17.Integrins in Kidney Epithelial Morphology 18.Integrin Cadherin Cross-Talk in Salivary Gland Development 19.Transgenic Organ Cultures 20.The Endothelium and Direct versus Indirect Allorecognition 21.B7 Blockade in Pediatric Renal Transplantation 22.Molecular Tools For Monitoring Immunosuppression Post-Transplantation 23.Training in Bioinformatics 24.Use of Artificial Intelligence to Monitor T cell activation and Immunosuppression efficacy. 25.Serum Cystatin C as a Marker of Glomerular Filtration 26.Oxidant and Antioxidant Levels in Children with Chronic Renal Insufficiency and End Stage Renal Disease 27.Prophylactic Urokinase Use in Hemodialysis Catheters
  10. 10. 28.Genetic Control of Podocyte Function 29.Alternatively Spliced Form of CTLA-4 and Genetic Susceptibility to Type 1 30.Diabetes 31.A Double-Blind Randomized Trial of Steroid Withdrawal 32.Use of Amlodipine in Children with Hypertension 33.Development of Cystic Renal Disease in Native and Transplanted Kidneys 34.Use of Enalapril in Children with Hypertension 35.Use of Growth Hormone in Dialysis Patients 36.Probabilistic Modeling of the Drug Development Domain 37.P-glycoprotein Function in Allograft Rejection 38.Melanoma Tumor Growth Inhibition and Chemoresistance Reversal in vivo Via Targeting of a Novel Human Multidrug Resistance P-glycoprotein Homologue 39.Role of PD-1 in Type 1 Autoimmune Diabetes
  11. 11. FACULTY AT CHILDREN’S HOSPITAL BOSTON, DIVISION OF NEPHROLOGY 1) William E. Harmon, M.D., Associate Professor of Pediatrics, Harvard Medical School and the Director of the Division of Nephrology of Children’s Hospital Boston, is the Training Program Director. Dr. Harmon’s clinical and research interests involve the pathophysiology and treatment of end-stage renal disease (ESRD) in children. Dr. Harmon has extensive experience in renal transplantation in children, especially infants and young children. Dr. Harmon is internationally recognized as a leader in pediatric organ transplantation. He served as the President of the American Society of Transplantation (AST) last year and is currently its immediate Past President. He is also the Chairman of the Transplant Advisory Group of the American Society of Nephrology and he serves on the Board of Directors of the International Pediatric Transplant Association (IPTA). Dr. Harmon’s prominence in Pediatric Transplantation led to his appointment as the first Chairman of the permanent Pediatric Committee of the United Network for Organ Sharing (UNOS) and eventual membership on its Board of Directors. He is a member of the DHHS Secretary’s Advisory Committee on Transplantation (ACOT) and is the Pediatric consultant to the Scientific Registry of Transplant Recipients (SRTR). Dr. Harmon’s particular interest pertains to immunosuppression to optimize successes following pediatric renal transplantation and to the promotion of organ donation initiatives. He recognized the need for multi-center trials to test pediatric hypotheses and thus, he was one of the earliest members of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). NAPRTCS was founded in 1987 and since that time has accumulated information on over 15,000 children with ESRD; this information has served as the basis for over one hundred manuscripts on all phases of treatment of CRI and ESRD. Dr. Harmon published the first analytical study from the NAPRTCS database and has been involved in most of its subsequent studies. He was named the President of NAPRTCS last year and has launched an important restructuring of the organization. Importantly, he developed the studies and protocols that were subsequently used as the basis for the development of the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT), which is sponsored by a U01 mechanism of the NIH. These trials, which have been ongoing for the past nine years, have been extremely productive and have been the basis of new techniques for provision of renal transplantation to children. One of the most innovative components of these studies is the description and analysis of intragraft gene expression of informative molecules. Dr. Harmon had collaborated with Dr. Terry Strom of the Beth Israel Deaconess Medical Center in the first description of these techniques in 1992. Subsequently, these techniques have formed the basis for defining the immune process in organ transplantation. Dr. Harmon is currently the Principal Investigator of the two multi-center clinical trials supported by CCTPT and serves as Chairman of its steering committee. Dr. Sayegh, the Research Director of the Division, serves as Co-Principal Investigator of the grant and he is in charge of coordinating the mechanistic and immunologic studies of study subjects. In addition to these scientific studies, Dr. Harmon has become actively involved in issues concerning organ donation and allocation, about which he has published multiple articles. He served as the Chairman of the Board of Trustees of the New England Organ Bank, one of the largest organ procurement organizations in the United States. He served as Chairman of the AST Public Policy Committee and, as noted above, he is currently the
  12. 12. only Pediatric specialty member of ACOT. Dr. Harmon also has extensive experience in the elements of pediatric dialysis, specifically urea kinetic modeling to monitor and prescribe hemodialysis treatments for children. He designed and directed the US multi-center trial of recombinant human erythropoietin in children undergoing chronic dialysis. Dr. Harmon has served on several NIH Study Sections evaluating and promoting transplant and dialysis research. He is one of the editors of Pediatric Nephrology, the only comprehensive textbook in the field. He is also an editor of Pediatric Solid Organ Transplantation. Dr. Harmon is an Associate Editor of the journal, Pediatric Transplantation. Throughout his clinical and academic career, Dr. Harmon has been actively engaged in education. He has been involved in the clinical training of every Pediatric Nephrology Fellow at Children’s Hospital Boston since his appointment as the Director of the Dialysis Program in 1979 and as Medical Director of the Renal Transplant Program in 1984. He was appointed Director of the Division of Nephrology in 1987 and assumed the directorship of the Fellowship Training Program and the Nephrology training grant at that time. He has engaged in individual sponsorship of clinical studies with over 50% of the fellows since he became Director of the Fellowship Training Program in 1987. Based upon these experiences, he has been asked to serve in advisory roles for other training programs. He has been a member of the Residency Training Committee and was one on the principal architects of the restructured Resident and Fellow Education Programs at Children’s Hospital Boston. He participated in the first Fellows’ Conference of the AST and served as Chairman of its Training and Manpower Committee. When he assumed Directorship of the Pediatric Nephrology Training Program at Children’s Hospital Boston, the program had been established but recruitment and training of fellows was unequal from year to year. He stabilized the program, assured that the program became vigorous and highly competitive, developed the first overall curricula and formed collaborations with neighboring institutions. He has been very successful in recruiting all of the biomedical scientists who now form the core of the Division of Nephrology Research Laboratories that form the basis of the research component of the Pediatric Nephrology Fellowship Training Program. In summary, Dr Harmon is an established local, national and international leader in the field of Pediatric Nephrology. He remains dedicated to the training of future leaders in the field and has established a program at Children's Hospital Boston that will serve that purpose. 2) David M. Briscoe, M.D. [Training Program Co-Director], Associate Professor of Pediatrics, Harvard Medical School: Dr. Briscoe's research involves detailed analysis of the mechanisms by which lymphocytes and endothelial cells interact with one another in the process of cell-mediated immune inflammatory reactions and allograft rejection. Studies involve the analysis of molecules, intracellular regulatory pathways and cytokines involved in the activation of T cells by endothelium. Dr. Briscoe’s laboratory has recently identified molecular pathways by which the endothelium can promote both direct and indirect pathways of allorecognition. The hypothesis currently being tested is that the endothelium promotes the indirect pathway of allorecognition and thus chronic allograft rejection. Dr. Briscoe’s laboratory has also identified that CD40-CD40Ligand interactions mediate Vascular Endothelial Cell Growth Factor (VEGF) expression and angiogenesis, as they pertain to allograft rejection. The hypothesis being tested is that CD40-CD40L interactions represent a link between the alloimmune response and angiogenesis, which facilitates the recruitment of
  13. 13. leukocytes into sites of inflammation, including allografts undergoing rejection. Dr. Briscoe has also investigated the role of VEGF- VEGF receptor interactions in immune inflammation and has determined that VEGF receptor mediated signals result in the expression of potent chemoattractant molecules in endothelial cells. His current studies are evaluating how VEGF might regulate chemokines and the relevance of VEGF-induced inflammation in alloimmunity. 3) Mohamed H. Sayegh, M.D., [Research Director], Associate Professor of Medicine, Harvard Medical School: Dr. Sayegh’s major research interests include the role and mechanisms of the "direct" and “indirect” pathways of allorecognition in rejection and tolerance. In the so-called "direct” pathway T cells recognize intact allo-MHC molecules on the surface of donor cells. Peptides, derived from endogenous proteins including MHC molecules, bound into the groove of the MHC appear to play an important role in this mode of allorecognition. In the so-called "indirect" pathway T cells recognize processed alloantigen presented as allopeptides by self antigen-presenting cells (APCs). These allopeptides are derived from allo-MHC molecules or from minor histocompatibility or tissue specific antigens. Dr. Sayegh has demonstrated that the indirect pathway occurs during allograft and xenograft rejection and plays an important role in the rejection process, especially in chronic rejection. His laboratory is currently focusing on studying the contribution of indirect allorecognition to the rejection process including establishing a TCR transgenic animal which is specific to Class II MHC allopeptides. In addition, human studies in his laboratory are focusing on developing novel assays to predict transplant outcome. Another major interest of Dr. Sayegh’s laboratory is investigating the role and mechanisms of T cell costimulation in transplantation and autoimmune diseases. Dr. Sayegh’s research studies focus on the role of CD28-B7 and CD40-CD40L families of costimulatory molecules in allograft rejection and autoimmune diseases, including diabetes. In addition, his studies focus on dissecting the mechanisms by which blockade of these pathways may prevent acute rejection and induce long term allograft survival and tolerance, and prevent and/or cure autoimmune diseases. 4) John Herrin, M.B.B.S. [Director of Dialysis Unit] Associate Professor of Pediatrics, Harvard Medical School: Dr. Herrin has long-standing experience in natural history of renal diseases and especially in glomerular and tubular disease. He has extensive experience in fluid and electrolyte balance in the critically ill patient (ICU and extensive burns) and the design of transplant immunosuppression in collaboration with the team at Massachusetts General Hospital and through participation in NAPRTCS. Dr. Herrin has an active interest in clinical research including studies on: a) autosomal recessive polycystic disease, b) growth and development in the patient with chronic renal disease, c) the role of steroids in treatment of renal disease and, d) cytokine effects in nephrotic syndrome and focal glomerulosclerosis in transplant patients. These interests provide a strong background for a mentorship role for fellows in training on the clinical services, including the general consultation and end stage renal program. Dr Herrin also has a close involvement in Harvard Medical School student teaching. 5) Jordan Kreidberg, M.D., Ph.D., [Director, Developmental Biology Research Laboratory], Assistant Professor of Pediatrics, Harvard Medical
  14. 14. School: Dr. Kreidberg’s research focuses on the signaling networks regulated by transcription factors and adhesion molecules that control mammalian development. The Wilms’ tumor-1 tumor suppressor gene is a zinc finger transcription factor required for development of the kidney and gonads. A combination of transgenic and molecular biological approaches are being used to understand its role in development and cancer. Transgenic mice expressing mutant forms of Wt1 in kidneys have suggested that Wt1 regulates the expression of growth factors that may regulate angiogenesis during organ development. Thus, the hypothesis that the regulation of angiogenesis has a crucial role in patterning developing organs is being pursued in the laboratory. The laboratory has also devised technologies to microinject and electroporate gene expression constructs into embryonic kidney organ cultures. This offers an alternate high-throughput means of transgenesis to study fundamental regulatory networks that establish pattern formation during early organ development. a3b1 integrin is a member of the integrin family of receptors. Similarly to how growth factor receptors transduce signals to cells as a consequence of binding secreted growth factors, integrins transduce signals upon interaction with components of the extracellular matrix. Thus, development and tumorigenesis are driven by the integrated signaling from growth factor receptors and integrins. Mice carrying a targeted mutation of the a3 integrin gene exhibit abnormal development of the kidneys, lungs, skin and brain. Cadherins are a second group of adhesion molecules that mediate cell-cell, as opposed to cell-matrix, interactions. The modulation of cadherin-mediated adhesion is of great importance in development and tumor progression. The laboratory is studying how integrin based signals regulate the function of the cadherin family of cell-cell adhesion receptors to affect cell morphology. Based on these findings using in vitro systems, studies are proceeding to design transgenic and conditionally gene-targeted mice to test how integrin-mediated regulation of cadherin function may affect development and tumorigenesis. 6) Michael Somers, M.D. [Clinical Director, Division of Nephrology], Assistant Professor of Pediatrics, Harvard Medical School: As Clinical Director, Dr. Somers is involved in all aspects of the clinical research program. He has significant interactions with pediatric renal fellows on our clinical service and has initiated several mechanistic studies with members of our research training faculty. Dr. Somers has been involved in the training of many renal fellows and pediatric residents through his clinical activities. His active clinical and research interests include: a) the characterization of specific immune responses to E. coli in hemolytic uremic syndrome; b) the role of vascular permeability factor (VPF, also known as VEGF) in the Nephrotic Syndrome and in the development of Focal and Segmental Glomerulosclerosis; c) bladder abnormalities in patients undergoing renal transplantation; and, d) methods for the evaluation and monitoring of continuous renal-renal replacement therapy in very young children. 7) Michelle Baum, M.D. Instructor of Pediatrics, Harvard Medical School: Dr. Baum has a strong focus on teaching and the training of fellows in clinical Nephrology. In addition, Dr. Baum has several clinical research interests pertaining to her involvement with the Myelodysplasia Program at the Children’s Hospital Boston. In this capacity, Dr. Baum has an interest in how bladder abnormalities might affect renal function and she is designing a registry to follow patients with myelodysplasia and assess factors that will predict long-term renal dysfunction. Dr. Baum has participated in several projects with the North American Pediatric Renal Transplant Cooperative
  15. 15. Study (NAPRTCS) involving the affect of native renal diseases, particularly FSGS, on renal transplant outcome. Dr. Baum is also involved in the analysis of data from centers participating in the Prospective Pediatric Continuous Renal Replacement Therapy registry. 8) Markus Frank, M.D., Instructor of Medicine, Harvard Medical School: Dr. Frank’s research interests concern the role of P-glycoprotein (P-gp) and related ABC transporters in immunity. Current projects in the laboratory include: a) the analysis of a role for P-gp in the alloimmune response. Dr. Frank has recently defined a novel role for P-gp as a switch in dendritic cell vs. macrophage differentiation. b) the analysis of a novel, third human P-gp family member. Dr. Frank has cloned a novel P-gp family member, which identifies a rare, stem cell phenotype-expressing cell subset among primary human melanocytes and malignant melanoma cells. This work involves a collaboration with the stem cell laboratory of Emanuela Gussoni of the Genetics department at Children’s Hospital Boston. 9) Nader Najafian, M.D , Instructor of Medicine, Harvard Medical School: Dr. Najafian’s major research interests include the development of clinical rejection/tolerance assays in renal transplantation: There is a great deal of interest in the concept of developing one or more clinical assays for monitoring immune status of transplant recipients. The focus of Dr. Najafian’s research involves the use of monitoring assays to evaluate tolerance following transplantation. His laboratory is focused on developing donor-antigen specific assays to measure alloreactivity. He has also been investigating the role of regulatory CD4+CD25+ T cells in renal transplant recipients: Dr. Najafian has demonstrated the existence of regulatory CD4+CD25+ T cells in a cohort of human renal transplant patients. He is currently studying the role of these cells in renal transplant recipients and exploring the possibility to expand these cells ex vivo. He is also interested in the role and mechanisms of T cell costimulation in transplantation and autoimmunity, with special focus on novel members of the B7-CD28 superfamily including ICOS-ICOSL, as well as PD-1 and its ligands, PD-L1 and PD-L2. 10) Thomas Natoli, Ph.D. Instructor of Pediatrics Harvard Medical School: Dr. Natoli’s research interest involves the role of Wt1 in renal development and in glomerular disease. Specifically, Dr. Natoli has generated Wt1-null ES embryonic stem cell lines and has used them to create chimeric mice for the analysis of Wt1 expression in vivo. Current research projects involve: a) evaluation of Wt1 in gonadal development. Chimeric mice generated in laboratory have demonstrated impaired spermatogenesis, with many seminiferous tubules devoid of spermatogonia. These data suggest that Wt1 is required in gonadal development. b) the role of Wt1 in glomerular- endothelial development. Dr. Natoli has generated transgenic mice that carry dominant-negative forms of the Wt1 gene under the control of the nephrin promoter. This promoter drives expression in the podocytes, the site of Wt1 expression in the adult kidney. Transgenic animals survived through E18.5, but were lost before weaning. E18.5 transgenic embryos demonstrated abnormalities of glomerular endothelial development. However, no change in expression of podocyte structural proteins was observed. Ongoing studies will address whether Wt1 regulates expression of angiogenic growth factors that play a role in glomerular endothelial cell development.
  16. 16. 11) Soumitro Pal, Ph.D. Instructor of Pediatrics, Harvard Medical School: Dr. Pal’s research interests involve signal transduction pathways involved in angiogenesis. Current research projects include: a) An analysis of the roles of oncogenes and protein kinases involved in the overexpression of vascular endothelial growth factor (VEGF), the most important angiogenic cytokine. b) The role of CD40 in angiogenesis. Dr. Pal has defined a novel CD40 inducible signaling pathway that is functional in VEGF expression and VEGF-induced angiogenesis. c) The role of VEGF-VEGF receptor interactions in inflammation. Dr. Pal has established that VEGF receptor-mediated signals are of importance for the expression of chemoattractant chemokines that facilitate the trafficking of leukocytes into sites of inflammation. 12) Elahna Paul, M.D., Ph.D., Instructor of Pediatrics, Harvard Medical School, Boston: Dr Paul’s research relates to the role of complement system in immunity. She is currently using gene complement knockout and transgenic mice in collaboration with Dr. Carroll to determine the effect of the complement system on early B cell development. She has developed a unique model for studying B cell tolerance by breeding C3, C4 and cr2 knockouts with a B cell transgenic mouse. Dr. Paul is currently focusing her studies on the effects of C4 defects on normal tolerization of autoreactive B cells. These studies will be applied to our understanding of human renal diseases in such as Lupus in which dysregulation of the complement system is associated with autoimmune kidney disease. 13) Nancy Rodig, M.D., Instructor of Pediatrics, Harvard Medical School: Dr. Rodig’s research interest is memory T-cell endothelial cell interactions. Her research projects involve the isolation and characterization of murine cardiac microvascular endothelium and the analysis of the phenotype of T-cells in regard to the expression of negative novel costimulatory molecules. She has also investigated the function of the endothelium in T-cell activation responses. She has recently begun clinical research studies involving translational mechanisms related to the outcome and treatment of pediatric patients with end-stage renal disease. 14) Asher Schachter, M.D., Instructor of Pediatrics, Harvard Medical School: Dr. Schachter’s research efforts focus on issues of Bioinformatics and artificial intelligence in pediatric renal disease. Dr. Schachter’s specific research focuses is to decipher the molecular mechanisms underlying pediatric nephrotic syndrome (NS) using bioinformatic tools. Pediatric NS is the most common glomerular disease in children and the most common acquired disease causing renal failure in children. NS represents a heterogeneous group of disorders, many of which are immune mediated and drug resistant. Therefore, this population of patients provides an excellent opportunity to study drug resistance at the molecular level, and to perhaps develop novel therapies. As well, of those children with NS who require renal transplantation, many will lose their allograft to recurrence of NS, suggesting that a systemic factor is pathogenic in this most severe subgroup of patients. Dr. Schachter’s research has provided some insight into the role of certain cytokines and transcription factors involved in NS. He is currently utilizing high-throughput techniques to study DNA, RNA and protein from NS patients in order to develop molecular models of NS pathogenesis and drug resistance. In addition, the development of novel therapeutic agents for transplantation benefits the pediatric NS population in that immunosuppressive agents have often been utilized off-label to treat steroid resistant NS and post-transplant recurrence of NS. To this end, Dr.
  17. 17. Schachter is focusing on transplantation genomics and decision analysis in drug development pertaining to immunosuppressive agents and the pediatric population. Dr. Schachter’s informatics-related skills include facility in programming (Java, PERL, R, SQL) and analysis of high-throughput gene expression data. Dr. Schachter is also experienced in the use of machine- learning models such as artificial neural nets and Bayesian networks to learn from datasets and to build predictive models in transplantation and immunology. Faculty outside the Division of Nephrology: 1) Joseph Bonventre, M.D., Ph.D., Professor of Medicine, Harvard Medical School, Boston: Dr. Bonventre is the Chief of the Renal Division at Brigham & Women’s Hospital. Dr. Bonventre’s major research interests are: a) the role of calcium, phospholipase A2 and lipids in signal transduction and cell injury; b) Cellular and molecular mechanisms of ischemic injury, programmed cell death, and renal repair; and c) Kidney transcription factors-their role in renal repair. Two proteins, KIM-1, an epithelial protein and nmb, a macrophage protein, are being studied to examine their roles in the response of the kidney to acute injury. A Kim-1 knockout/Gal4 knock-in animal has been derived to allow the use the promoter region of Kim-1 to express proteins specifically in the S3 segment of the proximal tubule, where most of the injury occurs. Transcription factor studies focus on a novel kidney- specific zinc finger transcriptional repressor, Kid-1, whose expression is regulated in renal ontogeny and by ischemia/ reperfusion was cloned and characterized by the laboratory a number of years ago. The Kruppel Associated Box-A (KRAB-A) motif of this and other zinc finger proteins was identified as a common repressor motif. A transcriptional repressor, KRIP-1, that interacts with KRAB-A has been cloned. A new family of proteins that associate with KRIP-1 (Trip-Br family) have been characterized which interact with E2F/DP1, two critical proteins for cell cycle regulation. This knowledge will aid in the understanding of the role that PLA2s play in injury and lead to better insight into mechanisms important for gene regulation governing cell proliferation, cell death and tissue repair after acute renal failure. 2) Michael C. Carroll, Ph.D., Professor of Pediatrics and Pathology, Harvard Medical School: Dr. Carroll’s research interest is in the role of the complement system in innate and acquired immunity and how it links the two systems via cell surface receptors. His laboratory has recently found that the complement system is critical in marking antigens with an activated fragment of complement C3 and in maintaining active self-tolerance in B cells. Dr. Carroll’s approach to understanding the biological importance of the many interactions is by construction of genetic models. For example, using gene targeting, he has generated mice deficient in several of the critical components, i.e. complement C3, C4 and receptors CR1 & CR2. By genetic reconstitution of these mice with transgenes bearing mutant forms of the protein or regulated by tissue specific promoters, novel insights into the complex complement system are being generated. 3) Michael Gimbrone, M.D., Professor of Pathology, Harvard Medical School: Dr. Gimbrone is the Chairman of the Department of Pathology at Brigham & Women’s Hospital. Dr. Gimbrone's research focuses on the mechanisms of
  18. 18. vascular disease, in particular the role of the endothelial cell in complex disease processes such as atherosclerosis, thrombosis and inflammation. He was among the first to establish reproducible methods for the in vitro culture of endothelium and smooth muscle from human blood vessels and to utilize the tools of modern cell biology and molecular biology to dissect their functions in health and disease. His laboratory has characterized the cytokine-activated endothelial cell as important in inflammation and atherogenesis. Most recently his group has focused on the molecular mechanisms linking biomechanical stimulation and endothelial gene regulation in atherogenesis. Dr. Gimbrone has published more than 250 research articles, book chapters and reviews in the field of vascular biology. He is a recipient of an Established Investigator Award from the American Heart Association and the Warner Lambert/Parke Davis Award in Experimental Pathology (FASEB). He is a Past-President of the American Society for Investigative Pathology, the founding President of the North American Biology Organization (NAVBO), and has served on the Board of Directors of FASEB, as well as various NIH study sections and national advisory committees. In 1993, he received the Basic Research Prize from the American Heart Association; in 1994, a MERIT Award from the National Heart Lung and Blood Institute and an unrestricted Cardiovascular Research Award from the Bristol-Myers Squibb Institute; in 1995, the Pasarow Award for Research in Cardiovascular Diseases. In 1997, he was elected to the National Academy of Sciences, and in 1999, to the American Academy of Arts and Sciences and the Institute of Medicine of the National Academy of Sciences. In 1999, he was a co-recipient (with Dr. Judah Folkman) of the J. Allyn Taylor International Prize in Medicine, recognizing his contributions to the establishment of the field of vascular biology. He currently serves as the Elsie T. Friedman Professor of Pathology at Harvard Medical School, Director of the Center for Excellence in Vascular Biology at the Brigham and Women's Hospital, and Chairman of the Department of Pathology at the Brigham & Women’s Hospital in Boston, Massachusetts. One major focus of study in the Gimbrone laboratory has been the molecular mechanisms that mediate the localized interactions of leukocytes with the vascular endothelium at sites of acute and chronic inflammatory responses, and vascular injury and repair. Our working concept has been that endothelium-dependent mechanisms (in particular, inducible cell surface adhesion molecules and secreted cytokines/chemokines, such as IL-8 and MCP-1) are important local determinants of the spatial and temporal patterns of leukocyte-vessel wall interactions. A second major focus of activity in the Gimbrone Laboratory (which has evolved from a long-standing collaboration with Prof. C.F. Dewey and colleagues in the Fluid Mechanics Laboratory at the Massachusetts Institute of Technology) is the study of hemodynamic forces, such as wall shear stress, as modulators of vascular endothelial structure and function. Specially designed in vitro flow devices are used to expose cultured endothelial monolayers to defined laminar, disturbed laminar, and turbulent flow regimens, and the resultant morphological, biochemical and molecular genetic changes are studied in the context of vascular adaptation, and also the pathogenesis of vascular diseases, in particular atherosclerosis. Finally, the Gimbrone Laboratory has undertaken a systematic approach to defining phenotypic modulation of vascular endothelium, in health and disease, utilizing state-of-the-art techniques for transcriptional profiling of endothelial gene expression, in vitro and in vivo. 4) Julie Ingelfinger, M.D., Professor of Pediatrics, Harvard Medical School: Dr. Ingelfinger currently directs the Pediatric Nephrology Laboratory at the Massachusetts General Hospital. She recently stepped down as the Director of Pediatric Nephrology at the Massachusetts General Hospital when she
  19. 19. joined the New England Journal of Medicine as an Associate Editor. Dr. Ingelfinger continues to work as a staff member and clinical Pediatric Nephrologist at the Massachusetts General Hospital. Her major research interest and the focus of her research involves the regulation and function of intrarenal renin-angiotensin systems. Current projects in her laboratory include: a) studies involving the intrarenal renin angiotensin system in the renal proximal tubule; b) the intrarenal renin angiotensin system in diabetes; c) the role of the renin angiotensin system in Fawn Hooded rats (a model of focal glomerulosclerosis); and, d) the role of maternal nutrition in renal development and the development of hypertension and mechanisms of proximal tubule injury. In addition, Dr. Ingelfinger has strong collaborative interactions with Dr. Eric Grabowski, Pediatric Hematology-Oncology Service in which she is studying the role of Shiga toxin in pathogenesis of the hemolytic uremic syndrome (HUS). 5) Raghu Kalluri, Ph.D., Associate Professor of Medicine, Harvard Medical School: Dr. Kalluri’s research interest is the understanding of the role of basement membranes in kidney disease. Basement membranes are specialized structures that are present in association with almost all cell types in the human body. Current projects in Dr. Kalluri’s laboratory involve: a) An analysis of the structure of basement membranes with a specific focus on different isoforms of type IV collagen, laminin and proteoglycans that bring about a unique tissue specificity; b) The analysis of glomerular and tubular basement membranes in the kidney and their relevance to many kidney diseases and fibrosis; c) An analysis of the molecular mechanism governing the progression of Goodpasture syndrome and Alport’s disease; and, d) The analysis of vascular basement membranes in angiogenesis. The vascular basement membrane constitutes an important component of a blood vessel and along with providing structural support, modulates capillary endothelial behavior, especially during the sprouting of new blood vessels. These studies resulted in the discovery of five new basement membranes, which have anti-angiogenic protein fragments. Some of these protein fragments are potent inhibitors of angiogenesis. e) The analysis of hepatocyte drug metabolism using liver specific basement membrane and matrices. 6) Isaac Kohane, M.D., Ph.D., Associate Professor of Pediatrics, Harvard Medical School: Dr Kohane, is the Director of the Children's Hospital Boston Informatics Program (CHIP) a multidisciplinary applied research and education program at Children's Hospital in Boston. CHIP focuses on both bioinformatics and clinical informatics. The faculty is diverse, including physicians with additional training in information science and computer scientists with expertise in the biological sciences. CHIP encourages collaboration and provides shared resources to develop innovative information technologies with the goal of both enhancing biomedical research and improving patient care. CHIP also serves as the bioinformatics core for several national genomics investigations. There are currently 15 CHIP faculty, nine CHIP fellows, five support staff and 3 students. CHIP funding comes from multiple sources and collaborations, including NLM, NIHGR, NCI, NHLBI, NINDS, NIDDK, and NIAID. Web-based & downloadable bioinformatics resources created and maintained by CHIP include SNPper, unCHIP, chipperDB, CAGED, BADGE, BEST, RelNet and CL-DNA (http://www.chip.org/chip2003/resources.cgi). CHIP bioinformatics research endeavors include development of statistical and computational techniques for analyzing gene expression data from microarrays under various experimental settings and for analyzing SNP (Single Nucleotide Polymorphism) data in performing large-scale association studies. CHIP staff also develop tools to integrate various databases effectively, and combine information from various
  20. 20. genomic and proteomic data to gain insights into biological pathways. Dr Kohane is also the Co-Director of the Harvard-MIT Division of Health Sciences and Technology Bioinformatics and Integrative Genomics training program, funded by NHGRI. He is a co-author of a popular textbook, “Microarrays for an Integrative Genomics” and an author on over 70 publications. Dr. Kohane supervises many research projects within CHIP, including reverse engineering of biological pathways, noise modeling of expression microarrays, gene clustering and classification, genomic applications to tumorigenesis, diabetes mellitus, neural development, and neuroendocrinology, personally controlled medical record systems, distributed medical record systems, and automated decision support. 7) Vijay Kuchroo, D,V,M, Ph.D. Associate Professor of Neurology, Harvard Medical School, Boston: Dr Kuchroos' major focus of research is the autoimmune T cell response. His research interests include the role of costimulatory molecules and their receptors in the induction and differentiation of T cells and regulation of autoimmunity. In addition, recently the laboratory has cloned novel cell surface molecules that are expressed exclusively on the surface of Th1 cells. One of the molecules appears to have a role in the macrophage activation and in mediating tissue destruction in autoimmune disease. The laboratory has primarily focused on studying the immune response to one of the major proteins of the CNS myelin namely myelin proteolipid protein (PLP). By using peptide-MHC binding strategy, a number of determinants in the PLP molecule that can induce an organ specific autoimmune disease, experimental autoimmune encephalomyelitis (EAE), have been identified. The T cell response to the encephalitogenic determinants of PLP in H-2 congenic mice has been analyzed, while some strains of mice are highly susceptible, other H-2 congenic strains are resistant to the development of disease. Genetic basis for the disease susceptibility and resistance has been analyzed by identifying genetic loci by genome wide scans, generation of congenic mice and identifying genes responsible for the phenotype. T cell receptor (TcR) transgenic mice that express TcRs that recognize various myelin antigens have also been generated in the laboratory and these mice develop spontaneous autoimmune disease on the susceptible but not on the resistant genetic background. The role of various costimulatory molecules and cytokines in the induction and regulation of autoimmune responses is under active investigation. We have previously demonstrated that the B7 costimulatory molecules play an important role in the T cell differentiation. The mechanism by which costimulatory molecules affect T cell differentiation is not well understood. Using yeast-two and yeast-three hybrid systems and intracytoplasmic tails of the costimulatory molecules, we have identified and cloned a number of novel molecules that may be involved in T cell differentiation and effector functions. 8) Andrew H. Lichtman, M.D., Ph.D., Associate Professor of Pathology, Harvard Medical School: Dr. Lichtman’s research interests relate to leukocyte-endothelial cell interactions in cell-mediated immune reactions and chronic disease. Current projects in Dr. Lichtman’s laboratory include the immunobiology of endothelial cells. His studies involve the analysis of functional interactions between the endothelium and T lymphocytes, the role of endothelial cells in antigen presentation and costimulation of T cells, and selective recruitment of T cell subsets into inflammatory sites. He is also investigating immune mechanism in atherosclerosis. Particular emphasis of his studies focus on T cell responses to atheroma antigens, mechanism of activation of plaque T cells, and the recruitment of leukocytes into
  21. 21. atherosclerotic lesions. Dr. Lichtman is also undertaking studies of the activation and effector functions of CD8+ T cell subsets cells in mouse models of autoimmunity (myocarditis), tumor immunity, and transplant rejection. 9) Martin Pollak, M.D., Assistant Professor of Medicine, Harvard Medical School: Dr. Pollack’s laboratory is working to identify genes involved in the development of focal segmental glomerulosclerosis (FSGS). FSGS is a common form of renal disease, seen both as an isolated entity and as a consequence of HIV infection, diabetes, obesity, and hypertension. Towards this goal, blood for DNA extraction and clinical analyses have been performed on members of approximately 90 families with an inherited form of this condition. The laboratory identified the first FSGS locus on chromosome 19q13. This locus was subsequently refined and demonstrated genetic heterogeneity of FSGS. Using careful analyses of genomic sequence databases, it was possible to identify a number of candidate genes in the FSGS-1 interval. Mutations have recently been found in ACTN4, encoding alpha-actinin-4, in FSGS-1 linked families. Because FSGS is also a cause of renal dysfunction secondary to multiple other diseases, the laboratory is examining the role of this FSGS gene as a candidate renal dysfunction susceptibility gene. Current efforts are underway to understand the function of ACTN4 and the mechanism of this form of kidney disease using mouse models and cell biologic approaches. Model organisms will be used to better define the biology of the mutant protein. The laboratory is also working to identify additional FSGS genes. 10) Terry Strom, MD, Director, Professor of Medicine, Harvard Medical School: Dr. Strom is the Chief of the Immunology Division of the Beth Israel Deaconess Medical Center. He has a long-standing interest in mechanisms of allograft rejection, the regulation of cytokine gene expression and tolerance induction. His research includes studies on transplant rejection and tolerance induction. Using molecular techniques, the characteristics of cells mediating rejection of grafts are under analysis. A focus of these studies are the role of Th1 and Th2 cells, regulatory cells, specific cytokines/growth factor requirements of lymphocytes and treatments that result in permanent graft acceptance. Other studies of human renal biopsies evaluate molecular markers of acute rejection and predictors of chronic rejection. He is also investigating immunoligands, immunosuppression and gene therapy. Various forms of IL-2, CTLA4, CD2 and IL-15 fusion proteins have been developed for use as specific immunosuppressive agents. These agents are designed to interfere with antigen-specific T cell activation by competitive inhibition of costimulatory signals or by targeted cell lysis. Studies are ongoing in transplantation experiments. Dr. Strom is also studying IL-15 receptor expression. The laboratory has found that IL-15 receptors are inducible upon activation mainly on T cells and macrophages. The effects of immunosuppressive drugs on IL-15 expression are currently being tested and preliminary data suggests that the IL-15 pathway of T cell activation is of importance in rejection. 11) Vikas Sukhatme, M.D., Ph.D., Professor of Medicine, Harvard Medical School: Dr. Sukhatme is the Chief of the Renal Division at Beth Israel Deaconess Medical Center. Dr. Sukhatme's laboratory focuses on four major areas: a) Renal Cell Carcinoma - A major program in the Sukhatme laboratory concerns renal cell carcinoma. A gene known as von Hippel-Lindau (VHL) is altered in over 70 percent of renal cell carcinomas, and introduction
  22. 22. of a wild type copy into these cells abrogates tumorigenicity. The laboratory has identified three growth factors -- vascular endothelial growth factor (VEGF), transforming growth factor-alpha (TGF-a) , and TGF-ß - whose genes are repressed by the VHL product. This explains why these genes are often upregulated in renal cell carcinoma and may contribute to tumorigenicity. Signal transduction pathways connecting VHL to VEGF, TGF- a, and TGF-ß are under investigation. Other novel gene targets for VHL have also been identified by differential display. In vivo therapy directed at antagonizing the action of TGF-ß suppresses growth of renal cell carcinoma. b) Anti- angiogenic Molecules and Mechanisms - A significant program in anti- angiogenic therapies in pre-clinical models of renal cell carcinoma is also underway. Soluble forms of endostatin, angiostatin, Kr5 and restin, a newly identified molecule, can now be produced in the laboratory, and their intracellular mechanisms of action are under study. A Phase I clinical trial aimed at inducing an anti-angiogenic state in patients with advanced malignancies but in good performance status is also underway utilizing a cocktail of tPA and captopril. c) Somatic Cell Gene Therapy - Somatic cell gene therapy to the kidney is a new area of investigation in Dr. Sukhatme's laboratory. Localization of a marker gene under different conditions of infection and in models of renal injury and disease are being assessed in the first phase of this work. Recently, vascular delivery in vivo has been achieved with adenovirus. The focus is on chronic renal injury (anti-fibrotic strategies) and on the genetic modification of a kidney allograft. d) Kidney Development - Another effort in Dr. Sukhatme's laboratory is to define the molecular basis for kidney development by characterizing a cascade of transcription factors that are critical in the induction of blastemal cells to form glomeruli and proximal and distal nephron segments. Studies have focused on a kidney- enriched transcription factor known as the Wilms' tumor suppressor gene product (WT1), which is necessary for kidney development. The WT1 gene was isolated from a region homozygously deleted in a Wilms' tumor cell line, based on conservation of the DNA sequence in different species and on hybridization of the clone to kidney RNA, supporting its activity in the tissue of interest. Factors regulating expression of WT1 are being studied in cell culture and transgenic mice. DNAse I hypersensitive sites and scaffold attachment regions have been identified in the WT1 gene locus, as an aid to identifying critical cis regulatory elements.