www.nida.nih.gov/researchtraining/Presentations/Sh...

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  • <number>
    Work by Eric Nestler at UT southwestern and others is examining the genetic, cellular and molecular mechanisms associated with chronic drug use. This research is showing that With initial drug use such as cocaine use Neurons emanating from the ventral tegmental area release dopamine on medium spiny neurons in the NAC.
    Repeated cocaine use and dopamine release there is an up regulation in the gene transcription factor delta fos B that is believed to result in morphological changes to dendrites and dendritic spines on these neurons.
  • <number>
    In fact research conducted by Terry Robinson at the university of Michigan shows that that repeated exposure to cocaine in rats leads to increased number of dendritic spines in the nucleus accumbens neurons and increased in dendritic branching.
    Taken as a whole this research shows that repeated exposure to drugs of abuse causes a cascade of events involving increased gene transcription in regions such as the nucleus accumbens that is believed to be responsible for actual morphological changes in dendrites and synaptic connections and plasticity leading to drug addiction.
  • <number>
    But, what we do not understand is why some people become addicted and others do not. We know from NIDA supported Twin studies that there is a heritable component to drug addiction.
    And now with the sequencing of the human genome we are able to ask what are the gene variants associated with drug addiction and what is their functional significance?
    We have taken a two-pronged approach to begin to answer this question:
    First NIDA’s intramural program is looking at genetic variants in heterogeneous populations of drug addicted individuals.
    Second our extramural research program through NIDA’s Genetic consortium and a contract with Perlegen Sciences has just completed a whole genome wide association study to uncover genetics variations associated with Tobacco dependence.
    A similar approach to uncover the genetic basis of disease now also moving forward under the NIH GAIN (Genetic Association Information Network) and GEI (Genes and Environment Initiative)
  • <number>
    So what this genome-wide association study is telling us is that Genes associated with drug addiction are those involved with many different aspects of synaptic function and synaptic plasticity and neuronal signaling.
    For example neurexin is a presynaptic cell adhesion protein that binds with neuroligin in synaptic formation and SYNAP-TO-TAG-MIN is involved in vesicle trafficking and neurotransmitter release.
  • From this research we are now showing that addiction is a complex behavioral, neurobiological and genetic Disorder.
  • New Pathways: This theme of the NIH Roadmap addresses the need to advance our understanding of the daunting complexity of biological systems. Future progress in medicine will require a quantitative understanding of the many interconnected networks of molecules that comprise our cells and tissues, their interactions, and their regulation
    Research Teams of the Future: NIH wants to stimulate new ways of combining skills and disciplines in both the physical and biological sciences
    Re-engineering the Clinical Research Enterprise is intended to address these pressing needs by promoting the better integration of existing clinical research networks, encouraging the development of technologies to improve the assessment of clinical outcomes, harmonizing regulatory processes, and enhancing training for clinical researchers. A major goal is to more fully involve and empower the public in the research process.
  • www.nida.nih.gov/researchtraining/Presentations/Sh...

    1. 1. Research Training Director’s Meeting November 3, 2006 Division of Basic Neuroscience and Behavioral Research (DBNBR) David Shurtleff, Ph.D. Director
    2. 2. DBNBR Goals Identify antecedents and consequences of drug abuse and addiction Develop and exploit new technologies, models, paradigms Identify genetic & developmental vulnerabilities for drug abuse Foster transdisciplinary/integrative research and training
    3. 3. Office of the Director David Shurtleff, PhD - Director Paul Schnur, PhD - Deputy Director Joni Rutter, PhD- Assoc Director Population & Applied Genetics Christie Baxter, BA – Program Analyst Amira Debbas, BA – Program Analyst Joyce Williams – Program Analyst Office of the Director David Shurtleff, PhD - Director Paul Schnur, PhD - Deputy Director Joni Rutter, PhD- Assoc Director Population & Applied Genetics Christie Baxter, BA – Program Analyst Amira Debbas, BA – Program Analyst Joyce Williams – Program Analyst Technology Development Karen Skinner, PhD Deputy Director for Science and Technology Development Technology Development Karen Skinner, PhD Deputy Director for Science and Technology Development Training Charles Sharp, PhD Special Assistant & Training Coordinator Beth Babecki, MA Deputy Training Coordinator Diane Lawrence, PhD Training Charles Sharp, PhD Special Assistant & Training Coordinator Beth Babecki, MA Deputy Training Coordinator Diane Lawrence, PhD Functional Neuroscience Research Branch Nancy Pilotte, PhD, Chief Jerry Frankenheim, PhD Diane Lawrence, PhD Geraline Lin, PhD Yu (Woody) Lin, PhD Functional Neuroscience Research Branch Nancy Pilotte, PhD, Chief Jerry Frankenheim, PhD Diane Lawrence, PhD Geraline Lin, PhD Yu (Woody) Lin, PhD Genetics and Molecular Neurobiology Research Branch Jonathan Pollock, PhD, Chief Christine Colvis, PhD John Satterlee, PhD Da Yu Wu, PhD Genetics and Molecular Neurobiology Research Branch Jonathan Pollock, PhD, Chief Christine Colvis, PhD John Satterlee, PhD Da Yu Wu, PhD Behavioral and Cognitive Science Research Branch Minda Lynch, PhD, Chief Tom Aigner, PhD Allison Chausmer, PhD Susan Volman, PhD Cora Lee Wetherington, PhD (Women’s Health Coordinator) Behavioral and Cognitive Science Research Branch Minda Lynch, PhD, Chief Tom Aigner, PhD Allison Chausmer, PhD Susan Volman, PhD Cora Lee Wetherington, PhD (Women’s Health Coordinator) Chemistry and Physiological Systems Research Branch Rao Rapaka ,PhD, Chief Paul Hillery, PhD Kevin Gormley Hari Singh, PhD Pushpa Thadani, PhD Dave Thomas, PhD Chemistry and Physiological Systems Research Branch Rao Rapaka ,PhD, Chief Paul Hillery, PhD Kevin Gormley Hari Singh, PhD Pushpa Thadani, PhD Dave Thomas, PhD Division of Basic Neuroscience and Behavioral Research
    4. 4. DRUGS BRAIN MECHANISMS ADDICTION ENVIRONMENT HISTORY - previous history - expectation - learning - social interactions - stress - conditioned stimuli - genetics - circadian rhythms - disease states - gender BIOLOGY Drug Addiction: A Complex Behavioral and Neurobiological Disorder
    5. 5. Dopamine Dendritic Spines Repeated Drug Abuse Increases Genetic Transcription Resulting in Long-term Structural Changes Adapted from Nestler E.J. Science & Practice Perspectives, 5(1) 2005.
    6. 6. Branches 60 55 50 45 11 10 9 8 CTLCTL COC CTL COCCTL COC Chronic cocaine increases density of dendritic spines and neuronal branching in the nucleus accumbens CTL COCCTL COCCTL COCCTL COC Robinson, T.E. & Kolb, B. Eur. J. of Neuro. 1999. Ferrario, C.R. et al. Biol. Psychiatry, 2005.
    7. 7. Drug Addiction is a Developmental Disease with High Prevalence in Adolescence NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003 Age 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% 1.8% 5 10 15 21 25 30 35 40 45 50 55 60 65 Percentageineachagegroupwhodevelop first - timedependence THC ALCOHOL TOBACCO
    8. 8. Highly Rewarding Effect of Nicotine/Acetaldehyde During Adolescence 0 1 2 3 4 5 Test Day Nic/Acet 30/16 µg (N = 6) Acet 16 µg (N = 6) Nic 30 µg (N = 10) Saline µg (N = 8) P90 Males Belluzzi, et al., Neuropsychopharmacology, 2005 Apr;30(4):705-12. * ** ** ** ** 0 10 20 30 40 0 1 2 3 4 5 Test Day MeanSelf-Injections(Nose-pokesin3hr) Nic/Acet 30/16 µg (N=11) Acet 16 µg (N = 8) Nic 30 µg (N=9) Saline 100 µl (N=7) P27 Males
    9. 9. Drug Addiction Is Influenced by Interactions of Genes and Environment Twin studies consistently show that there is a heritable component to drug abuse and addiction. What are the gene variants? Extramural Study NIDA/Perlegen/WashU Whole Genome Scan for Nicotine Addiction Intramural Study NIDA Affymetrix 500K screen for Drug Addiction
    10. 10. Many of These Genes Have Synaptic Functions Dean and Dresbach, TINS, 2006 { presynaptic postsynaptic { De Camilli et al, 2001 Dendritic Spines CELL ADHESION NEURO- TRANSMISSION SIGNAL TRANSDUCTION TRANSCRIPTION FACTORS
    11. 11. Genome-wide association scans Gene variants What is the functional significance? Need: Functional validation of gene variant Capitalize on: NIH Knockout Mouse Project High-throughput genetic and RNAi methods Research in GEI (FY11&12) Use genetic models to: Investigate mechanisms of drug dependence Test potential therapeutics Functional Genomics
    12. 12. Addiction is a Complex Behavioral, Neurobiological, and Genetic Disorder ENVIRONMENT & DRUG EXPOSURE SYNAPTIC PLASTICITY BRAIN CHANGES GENETIC VARIANTS
    13. 13. DBNBR Research Training
    14. 14. Framework to enhance cooperative activities among 16 NIH Institutes and Centers Take on challenges in neuroscience that are best met collectively Develop research tools and infrastructure that will serve the entire neuroscience community Research Training Programs Training in Neuroscience Imaging (Steve Grant, PO) Computational Neuroscience (Susan Volman, PO) Neurobiology of Disease (Beth Babecki, PO) Jointly Sponsored Predoctoral Program in the Neurosciences (JSPTPN) (Beth Babecki, PO)
    15. 15. NIH Roadmap FOR Medical Research TransNIH initiative for a more efficient and productive system of medical research Identifies themes in three main areas for support: New pathways to discovery Research teams of the future Re-engineering the clinical research enterprise • NIDA lead on Interdisciplinary Research Training initiative – Support didactic and research experiences designed to provide students with the knowledge and research experiences necessary to develop interdisciplinary solutions – Allison Chausmer (lead program officer)
    16. 16. Career Development Plan Yes Do I have pilot data? No No Apply for R03, BSTART or ISTART Do I need more training or changing career emphasis? Institutional Pre-Doctoral Fellowship-T32 Pre-Doctoral Fellowship-F31 Post-Doctoral Fellowship-F32 Institutional Post-Doctoral Fellowship-T32 R01 Yes Apply for Mentored K ** ** ** * Contact Program* Contact Program
    17. 17. Mentored Career Development Awards Mentored Research Scientist Development Award (K01) NIH Pathway to Independence (PI) Award (K99/R00) Mentored Clinical Scientist Development Award (K08) Mentored Quantitative Research Career Development Award (K25) Mentored Patient-Oriented Research Career Development Award (K23)
    18. 18. Progress Review of T32s Trainee progress (publications, placement, mentors) Program features and changes (breadth, student diversity, scientific diversity) Interactions Scientific Career development Use of slots (level, length, throughput, transition to independence) Contingency planning for gaps in funding (last year of T32)- Looking beyond supplements
    19. 19. Enhancing the Training Experience Scientific Meetings NIDA/SfN Mini-convention Poster presentation Travel awards Networking CPDD/ INRC/ SNIP etc. training mixers NIDA/SfN Mini-convention/NIDA exhibit Grantsmanship CPDD Grant writing workshop/tutorial SFN NIH Professional “Survival” Skills Workshop NIDA-supported Scientific Training Cold Spring Harbor Summer Institute Woods Hole
    20. 20. DBNBR Training Coordinators Charles Sharp: csharp1@nida.nih.gov - - 301-443-1887 Beth Babecki: bbabecki@nida.nih.gov 301-443-1887 Diane Lawrence: LawrenceDi@nida.nih.gov 301-443-1887

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