Division  of  Basic  Neuroscience  &  Behavioral  Research:    

 AN  OVERVIEW  of  NIDA’s    DISCOVERY  PROGRAM  

Joni  Ru(er,  PhD  NIDA  Council  May  7,  2014  

 

NIDA's  mission  is  to  lead  the  Na;on  in  bringing  the  power  of  science  to  bear  on  drug  abuse  and  addic;on    

           

Advancing the Science of Drug Addiction Through Basic Research

DBNBR  

Func;onal    Neuroscience  Research  

Chemistry  &  Physiology  Research  

Gene;cs  &    Molecular  

Neurobiology  

Behavioral  &    Cogni;ve  Research  

HIV/AIDS,  Pain,  Sex  Differences,  Training  

Cu=ng  Edge  Basic  Research  Award  

(CEBRA)   Drug  Supply  Program  

Early  Career  Award  in  Chemistry  of  

Drug  Abuse  (ECHEM)  Trans-­‐NIH  InteracOons  

NIDA  GeneOcs  ConsorOum  &    Repository  

Direct,  coordinate,  and  support  Division’s  mission  &  acOviOes:        1)  Strategic  DirecOons  &  analysis      2)  Goals  through  our  branch  structure      3)  Trans-­‐NIDA  and  NIH  acOviOes  

   

   

       Joni  L.  RuQer,  PhD  –  Director  Roger  Li(le,  PhD–  Deputy  (June  1)    

Mark  Caulder,  MS,  MPH    

Training  &  Career  Development  Beth  Babecki,  MA  

Roger  Sorensen,  PhD    

SBIR/STTR  Coordinator  Kristopher  Bough,  PhD  

 Common  Fund  &  Blueprint  

John  Sa(erlee,  PhD  Dena  Procaccini,  MA  

 

Division  of  Basic  Neuroscience  and  

Behavioral  Research    

Analysis  &  Support  ChrisOe  Espinoza  Dawnya  Jordan  Gail  Pointer  

Myriam  Selmane  Joyce  Williams  Shyra  Witcher  

DBNBR  OD    

Iden;fy  behavioral  processes  that  underlie  drug  addic;on  

BCSRB  Strategic  Direc;ons:    •  IdenOfy  how  environmental  variables  and  behavioral  phenotypes  

influence  risk  and  predicOon  •  Develop  paradigms  that  model  the  complexity  of  human  addic;on  •  Develop  intervenOons  to  change  behavioral  trajectories  of  addicOon  •  Examine  neurobiological  correlates  and  mechanisms  of  abuse-­‐related  

behaviors  

       

Minda  Lynch,  PhD  –  Chief  Susan  Volman,  PhD  Shelley  Su,  PhD    J  

Initiation

Escalation Abstinence Relapse

Modeling the Human Phases of Drug Abuse and Addiction

Maintenance

IncubaOon  

Sign Trackers (STs) approach and contact the lever reliably, avidly and quickly

Goal Trackers (GTs) do not approach or contact the lever

Individual Differences in Incentive Salience

ST/GT represent a complex behavioral phenotype that get at intrinsic factors that drive behavior: impulsivity (STs are more impulsive) and attention (STs have

difficulty focusing and sustaining attention à drug abuse vulnerability

Using  Behavioral  Models  to  Improve  Preven;on    

and  Treatment  Tes7ng  Pharmacologic  Interven7ons  

       

•  Facilitate  exOncOon:  D-­‐cyclosporine  •  HPA  Axis:  CRF  receptors  

Tes7ng  Behavioral  Interven7ons    •  CondiOoned  inhibiOon  •  Deepened  exOncOon  •  Reverse  habits  •  Impulse  control  •  Reduce  cue  associaOons  

Tes7ng  Environmental  Interven7ons    

•  Exercise  •  Enrichment  •  Social  InteracOon  •  AlternaOve  rewards  •  DBS    

Developmental  Stage  (esp.    adolescence)  

Gene;cs  Addic;on  Trajectory  

Sex  Differences  

Important  ConsideraOons:  Social  Interac;ons  

Combined  Voltammetry/Electrophysiology    in  Behaving  Rats  

Regina  Carelli  (PI)  and  Mark  Wightman  -­‐  CEBRA  

R21    2001-­‐03  R01    2004-­‐14  

50  µm  

25  µm  

DA  DA  

DA  

DA  

The  Promise  

The  Payoff  

Montague  &  Phillips  DA  release  in  humans  

Simultaneous  recording  of  fast  DA  signaling  and  electrophysiology  through  same  electrode  

Awake,  cocaine-­‐  seeking  rats  

SCIENCE  VOL  344  2  MAY  2014  

cue  

Lever    press  

Iden;fy  the  func;onal  proper;es  of  neural  circuits  affected  by  repeated  intermiQent  drug  use          

FNRB  Strategic  Direc;ons:        •  Determine  the  interacOons  of  drug  exposure,  development,  and  

microenvironment  in  shaping  neural  circuits  •  Map  primary  and  compensatory  connec;ons  and  adaptaOons  in  neural  circuits    •  IdenOfy  the  drug-­‐related  glia-­‐neuronal  adapta;ons  

Nancy  PiloQe,  PhD  –  Chief  Roger  Sorensen,  PhD  

 

Func;onal  Changes  Occur  Over  Time  Basis  for  Incuba;on?  

Wolf  lab:    Neuropharmacology,  2014,  76PtB:287-­‐300  

NAC  is  Point  of  Convergence  that  Influences  Rewarding  Behaviors—But  Which  Neurons  Are  Needed?  

Guan  et  al,  Intl  J  Obesity,  2012  

Bringing  technology  to  our  sophisOcated  behavioral  models  of  addicOon  

Gene;c  Tools  Define  Circuits  •  Optogene;cs:    SOmulates  gene;cally  altered  neurons  and  record  from  targets  simultaneously  

Tye  and  Diesseroth,  Nat.  Neuroscience,  2012  

Gene;c  Tools  Define  Func;on  DREADDS:    Designer  Receptor  Exclusively  AcOvated  by  Designer  Drug  

CNiFERs:    Cell-­‐based  Neurotransmi(er  Fluorescent  Engineered  Reporters  

TargeOng  receptors  Use  in  vivo:      to  monitor  or  influence  funcOon  Use  in  vitro:    to  screen  possible  medicaOons  

Silencing  synapses  

Adapted  from  Bryan  Roth,  UNC  

In  progress,  adaptaOon  for  imaging  deep  brain  regions  

Adapted  from  David  Kleinfeld,  UCSD  Supported  by  NIDA  CEBRA  

Determine  the  molecular  and  cellular  basis  of  addic;on  vulnerability  

GMNRB  Strategic  Direc;ons:    •  IdenOfy  genes  and  gene;c  varia;ons  and  their  funcOons  •  IdenOfy  epigene;c  and  non-­‐coding  regulators  of  gene  expression  •  Use  systems  approaches  to  understand  molecular  interacOons  •  IdenOfy  molecular  determinants  of  HIV  latency  modified  by  drugs  of  abuse  

       

Jonathan  Pollock,  PhD  –  Chief  John  Sa(erlee,  PhD  Da-­‐Yu  Wu,  PhD   Gene;cs  &  Molecular  

Neurobiology  Research    

 

Iden;fica;on  of  Genes  Involved  in  Astrocyte  Forma;on,  Func;on,  &  Elimina;on  

(modified  from  Ben  Barres  MERIT  Awardee)  

FormaOon  (+  Maintenance)  

Gpc4,6 PostsynapOc            funcOon  

C1q EliminaOon      

C1q EliminaOon      

NIDA  GeneOcs  ConsorOum  &  DNA  Repository  

Over  53,000  well-­‐characterized  DNA      samples  for  GWAS  and    other  studies    

CYP2A6  

IPO11/5HT1A  CHRNB3/CHRNA6  

CHRNA5/CHRNA3/CHRNB4  

SNP-­‐trait  associaOons  with  p-­‐value  ≤  5.0  ×  10-­‐8  

Fowler  et  al.  Nature.  2011  Mar  31;471  Piccio(o  et  al.  Nature  391,  173-­‐177,  1998  

β2-­‐/-­‐  

WT  

Rewarding  effects  –  β2  KO   Aversive  effects  –  α5  KO  

NicoOne  rewarding  and  aversive  effects:    MulOple  paths  towards  nicoOne  addicOon  

The  Drug  Abuse  &  Addic;on  Gene;cs  Research  “Engine”    

 HUMAN  GENETICS  

Discover  new  human            genes/variants  

MOLECULAR  GENETICS  

Neurobiology  &    FuncOon  

Discover  new    genes/variants  using    relevant  model  organisms  

New  candidate  genes  For  human  studies  

Epidemiology  &  Exposure  

Clinical  &  PharmacogeneOcs  

IdenOficaOon  à  ReplicaOon  à  FuncOon  à  Causality  à  Clinical  UOlity  

Behavior  

Environment  &  Development  

DBNBR  SBIRs:  NMR  &  Genotyping  

•  Siloam  Biosciences  – NicoOne  Metabolic  RaOo  (NMR)  =  3HC  /  coOnine  

– Biomarker  for  CYP2A6  acOvity  &  geneOc  variaOon  

– POC  diagnosOc  biomarker  for  smoking  cessaOon  

– Phase  II  complete  à  Applying  for  Ph  IIB  (Aug  5)  

•  BioRealm,  LLC  

–  Smokescreen®  =  SNP-­‐based  genotyping  array  ,  Phase  II  

–  SNPs  related  to  addicOon,  the  consequences  of  smoking,  and  smoking  cessaOon,  populaOon  structure  

–  CollecOng  pilot  genotypic  data  for  technical  validaOon  of  array  

–  Working  with  RUCDR.org  to  lay  the  groundwork  for  development  of  CLIA-­‐based  lab  test  

ZFP-­‐bi-­‐Directed  Control  of  ∆FosB  Expression  in  NAc  Regulates  Cocaine-­‐Elicited  Behaviors  

Adapted  from  Heller  et  al.,  submi(ed  

More DNA methylation Less histone acetylation Compressed chromatin Decreased gene expression

Less DNA methylation More histone acetylation Expanded chromatin Increased gene expression

Characterize  receptors  and  develop  ligands    to  accelerate  target  iden;fica;on  

CPSRB  Strategic  Direc;ons:    •  Isolate  target  receptors  and  endogenous  ligands,  validate,  &  test  •  Emerging  drug  targets  for  tobacco  addicOon  through  regulaOon  of  the  

cannabinergic  system  •  Discovery  of  bioac;ve  lipids  in  addicOon  and  health  •  Support  computa;onal  modeling  

       

Rao  Rapaka,  PhD  –  Chief  Kristopher  Bough,  PhD  

Paul  Hillery,  PhD  Vishnudu(  Purohit,  PhD  

Hari  Singh,  PhD  

 

Chemistry  and  Physiological  Systems  

Research    

X-­‐Ray  Crystallographic  Structures  of  Opioid  Receptors      

X-­‐Ray  crystal  structure  of  the  µ-­‐opioid  receptor  bound  to  a  morphine  antagonist  

}  1984              à  NIDA  Conference  on  opioids  for  drug  development  }  1994              à  X-­‐Ray  structure  likely  to  be  elucidated  ≤  10  years  }  2012              à  X-­‐Ray  structures  for  µ,  δ,  κ  and  OF/Q  receptors  }  2012-­‐            à  Agonist  development  and  funcOonal  selecOvity  

R01  DA36246    (MERIT  Award:  R37)  “Structural  Basis  of  Opioid  Receptor  FuncOon”  

Ray  Stevens    (P01  DA035764)    κ-­‐opioid  receptor  

Opioids:    A  Strategy  to  Improve  Side-­‐Effect  Profiles    

}  BendaviaTM  (SS-­‐31)  currently  in  Phase  II  clinical  trials  for  heart  failure  and  acute  kidney  failure—Sponsored  by  Stealth  PepOdes    

q  [Dmt1]DALDA  is  a  BBB-­‐permeable,  mulO-­‐funcOonal,  highly  posiOvely  charged  tetrapepOde  

q  Schiller-­‐Szeto  PepOdes  are  “Druggable”  •  Pass  through  BBB      •  Act  as  cell-­‐penetraOng  drug  delivery  molecules  •  Mitochondria  permeable;  Strong  anO-­‐oxidant    

 

DieOs  et  al.  Br  J  Anaesth.  2009  

DBNBR  cannabis  porzolio  

Drug  Supply  Program  

Brain  NeuromodulaOon  Neuroimmune    

HIV  Pain  

Molecular  &  Cellular  Brain  Development  

GeneOcs  &  EpigeneOcs  

Chemistry  &  Physiology  Probes,  ligands  

 SAR  

IRP  Adult  male  offspring  with  parental  adolescent  THC  exposure  have  increased  moOvaOon  to  self-­‐administer  heroin  

Behavior  SA;  Reinforcement  

Transgeneratonal  effects  

NIDA  Drug  Supply  Program  (DSP):      Compounds  in  Each  Cannabinoid  Class  

•  Cannabichromene  –  2  •  Cannabicyclohexanol  –  3  •  Cannabidiol  –  2  •  Cannabigerol  –  1  •  Cannabinol  –  3  •  Enzyme  Inhibitors  –  3  •  Fa(y  acid  derivaOves  

(Annandamide)  –  4  •  Fa(y  acid  derivaOve  

(Arachidonyl  analogs)  –  2  •  Fa(y  acid  derivaOves  

(Arachidonyl  esters)  -­‐  4    

•  Fa(y  acid  derivaOves  (Palmitoyl  amides)  –  2  

•  Indole  analogs  &  Related  –  18  •  Precursors,  BiosyntheOc  –  3  •  Precursors,  SyntheOc  –  1  •  Pyrazole  class  –  4  •  Tetrahydrocannabinol  class  –  

51  •  SyntheOc  cannabinoids  -­‐  16  

DSP  Chemicals  and  research  probes  •  Unavailable    

•  Difficult  to  obtain  •  Very  expensive  

•  AnalyOcal  services  

Promote  cross-­‐cuong  NIDA  priori;es  through  basic  science  

   

DBNBR  Strategic  Direc;ons:      •  HIV  and  addicOon  •  Sex/gender  differences  in  addicOon  vulnerability  •  Chronic  pain,  addicOon  liability,  drug  target  idenOficaOon,  pharmacogenomics  •  Training  programs  that  foster  career  development  

       

Pain  Vishnu  Purohit  

Sex  Differences  Nancy  Pilo(e  

Training  Beth  Babecki  (Ts/Fs)  Roger  Sorensen(K99s)  

HIV/AIDS  Vishnu  Purohit  

Promote  cross-­‐cuong  NIDA  priori;es  through  basic  science  

   

DBNBR  Strategic  Direc;ons:      •  HIV  and  addicOon  •  Sex/gender  differences  in  addicOon  vulnerability  •  Chronic  pain,  addicOon  liability,  drug  target  idenOficaOon,  pharmacogenomics  •  Training  programs  that  foster  career  development  

       

Pain  Vishnu  Purohit  

Sex  Differences  Nancy  Pilo(e  

Training  Beth  Babecki  (Ts/Fs)  Roger  Sorensen(K99s)  

HIV/AIDS  Vishnu  Purohit  

DBNBR  Training  Programs  

29,  11%  

137,  53%  

92,  36%  

DBNBR  Fellowships:    Predoctoral  and  Postdoctoral  

F30  (MD/PhD  Predoc)  

F31  (Predoc)  

F32  (Postdoc)  

•  K99/R00  Pathway  to  Independence  Award  

•  Over  last  6  years:    –  92  invesOgators    –  138  K99  applicaOons  

•  50  K99  awards  •  receiving  awards  =  36.2%  

N=319  

22  DBNBR  Training  Grants  (T32s)  

K99  Awards  2007-­‐2010  Status  of  Applicants  in  2014  

0  

5  

10  

15  

20  

25  

30  

Awarded  K99  

Unsuccessful  K99  Applicants  

Post  K99/R00  

Being  a  K99  Awardee    Predicts  Success!  

FOAs  for  Applied  Basic  Med  Chem:  ECHEM  and  beyond  

ECHEM  

ECHEM  

ECHEM  

ECHEM  

This  Funding  Opportunity  Announcement  (FOA)  seeks  to  facilitate  the  entry  of  new-­‐to-­‐NIH  invesOgators  into  basic  chemistry  research  applied  to  drug  abuse  and  addicOon.    

Single Cell

Analysis

Current  Common  Fund  Programs  

Increasing the Diversity of the NIH-Funded

Workforce

PROMIS: Clinical

Outcomes Assessment

NIH Center for

Regenerative Medicine

Regulatory Science

Molecular Libraries

and Imaging

Human Microbiome

Protein Capture

Pioneer Awards New Innovator Awards Transformative Research Awards Early Independence Awards Structural

Biology

Bioinformatics and Computational Biology

Building Blocks, Biological Pathways

And Networks

Genotype- Tissue

Expression

Library of Integrated Network-

Based Cellular Signatures

(LINCS)

Nanomedicine

Science of Behavior Change

Gulf Oil Spill Long Term Follow Up

Global Health

Knockout Mouse

Phenotyping

NIH Medical Research Scholars

Bridging Interventional Development

Gaps (BrIDGs)

Big Data to Knowledge

(BD2K)

HCS Research Collaboratory

High-Risk Research

NIH Common Fund

Health Economics

ExRNA Communication

h(p://commonfund.nih.gov/    

Metabolomics

Undiagnosed Diseases Program

Extracellular RNA Communication Strengthening

the Biomedical Research

Workforce

Illuminating the Druggable Genome Epigenomics

New  (type  1  or  2)  funded  epigene;cs  project  grants  

0  

5  

10  

15  

20  

25  

30  

35  

40  

45  

50  

2005   2006   2007   2008   2009   2010   2011   2012   2013   2014  

Common  Fund  NIDA  

CF  Epigenomics                launched  

2006  NIDA    Epigene;cs    RFA  

#  new    funded    grants    

What’s  next  for  DBNBR  

Energe;cs    DNA  and  RNA  modifica;ons  Transgenera;onal  effects  

 Computa;onal  neuroscience  Imaging  &  gene;cs  

CRISPR-­‐Cas9/TALEN/ZFN  Pharmacogene;cs  Cannabinoids  Novel  Targets  

Avenir Award Program for Genetics or Epigenetics of Substance Abuse (DP2) RFA-­‐DA-­‐15-­‐006  August  18,  2014,  2015,  &  2016  

Effects of Cannabis Use and Cannabinoids on the Developing Brain PA-­‐14-­‐163; Standard  dates    

Identification of Gene Variants for Addiction Related Traits by Next-Gen Sequencing in Model Organisms Selectively Bred for Addiction Traits PAR-­‐14-­‐010;  June  30,  2014,  2015,  &  2016;  October  31,  2015,  2015  

Neuroimmune Signaling and Function in Substance Use Disorders PA-­‐14-­‐084;  Standard  dates    

Neuroscience Research on Drug Abuse PA-­‐13-­‐338;  Standard  dates  

Discovering Novel Targets: The Molecular Genetics of Drug Addiction and Related Co-Morbidities PA-­‐14-­‐025;  standard  dates  

Functional Genetics, Epigenetics, and Non-coding RNAs in Substance Abuse PA-­‐14-­‐013;  standard  dates  

Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects PAR-­‐14-­‐106;  standard  dates  

Simplified  Neural  Circuitry  

To  Complexity  of  the  Connectome  

And  Behavior  

Ligands,  Probes,  &  Compounds  

Novel  Targets  in  Gene;cs  &  Epigene;cs  

Managing  &  Integra;ng  Basic  Science  Research  to  Advance  the  Science  of  

Addic;on  

ScienOfic  Community   ScienOfic  MeeOngs  Literature  NIDA   Other  

BCS  

CPS  

FN  

GMN  

NIDA  SBIR  FOAs   PI  CollaboraOons  

Division  of    Basic  

Neuroscience  

#  =  Funded  RPGs  

GM  –  Porzolio  Dashboard  

Special  thanks  to  Dr.  Jose  Ruiz,  OEA  

THANK  YOU  

Extra  slides  

CollaboraOons  Inter-­‐Divisional  

 

Target  ID  Assay  Devel  

Screen  to  Hit  (HTS)  

Hit  to  Lead  

Proof  of  Principle  (Lead  Valid)  

Lead  optimization  

Preclinical  Development  (Safety/Tox)  

Clinical  Trials  

Functionalization   Protein  Prioritization   Phase  I   Phase  

II  Phase  III  

                     DBNBR  –  PI-­‐initiated  RPGs  

DPMC  –  Grand  Opportunities  in  Medications  Development  for  SUDs  (U01)  

DPMC  –  Med  Development  Centers  of  Excellence  Cooperative  Program  (U54)  

DPMC  –  Strategic  Alliances  for  Med  Development  (R01)  

DBNBR  -­‐  Early  Career  Award  in  Chemistry  and  Drug  Abuse  and  Addiction  (eCHEM)  (R21/R33)  

SBIR  /  STTR  Program  (R41/R42)  (R43/R44)  

PublicaOons  by  Journal  Impact  Factor  and  Branch  

1444,  63%  

795,  34%  

68,  3%  

GMN  

top  10%    

top  60%    

bo(om  40%  

656,  44%  

832,  55%  

12,  1%  

BCS  

top  10%    

top  60%    

bo(om  40%  

990,  51%  946,  48%  

19,  1%  

CPS  

top  10%  

top  60%  

bo(om  40%  

850,  53%  

740,  46%  

10,  1%  

FN  

top  10%  

top  60%  

bo(om  40%  

CRISPR/Cas9;  TALEN;  ZFN  Next  Gen  Transgenics  

•  CRISPR  enables  the  genera;on  of  gene;cally  modified  rodent  and  non-­‐rodent  animal  models      

               (Yuyu  Niu  et  al.  (2014)  Cell  156,  1-­‐8)    

•  CRISPR  enables  mul;ple  gene;c  manipula;ons  in  mice  in  parallel    

         (Haoyi  Wang  et  al.  (2013)  Cell  153,  910–918)    

 Eroom’s  Law:  rocesses  that  are  ge=ng  steadily  slower  and  more  difficult  with  Ome.  

which  describes  a  long-­‐term  trend  in  the  computer  hardware  industry  that  involves  the  doubling  of  'compute  power'  every  two  years  

Cu=ng-­‐Edge  Basic  Research  Award  (CEBRA  R21)  

What  is  the  purpose  of  the  CEBRA  program?  •  To  foster  highly  innovaOve  or  conceptually  creaOve  research  related  to  drug  abuse  and  addicOon.  

•  To  Support  research  that  is  high-­‐risk  and  potenOally  high-­‐impact  that  is  underrepresented  or  not  included  in  NIDA's  current  porzolio.    

•  To  solicit  projects  that:  •  Test  a  highly  novel  and  significant  hypothesis  which,  if  confirmed,  would  have  a  substanOal  impact  on  current  thinking;  and/or  

•  Develop  or  adapt  innovaOve  techniques  or  methods  for  applicable  to  addicOon  research.  

Who  is  the  CEBRA  for?  •  Drug-­‐abuse  research  invesOgators  who  wish  to  develop  or  adapt  new  methods  or  techniques  or  test  novel  hypotheses.  

•  InvesOgators  with  experOse  in  fields  other  than  drug  abuse  who  wish  to  establish  new,  innovaOve  research  programs  relevant  to  drug  abuse.      

BC  –  Porzolio  Dashboard    

StaOsOcs  

 CEBRAs  submi(ed  9/01-­‐4/14  616    CEBRAs  funded  FY2001-­‐2014  233  

 By  Division  

 DBNBR   206  

 DCNBR   16  

 DPMCDA   10  

 DESPR   1  

e.g.  HapMap  and  1000Genomes  

e.g.  Longitudinal    Studies  

e.g.  Case/control  studies  

   

Genotypic  InformaOon  

Phenotypic  InformaOon  

CHRNA3   CHRNB4  

Chromosome  15   rs16969968  

CHRNA5  

ASW  

YRI  

CEU  

rs16969968  

α5   β4  α3  

0  

5  

10  

15  

20  

25  

2005-­‐2007   2008   2009   2010   2011   2012  

AddicOon  

NicoOne  

Alcohol  

Year  

Num

ber  o

f  pub

licaO

ons  

A.   B.  

C.  

D.  

Sarda  S  and  Hannenhalli  S.  2013  

Cannabinoid  Research  Advances    

Structural  adaptaOons  in  a  membrane  enzyme  that  terminates  endocannabinoid  signaling  

}  1986              à  Cannabinoid  Conference    }  1987              à  Monograph  developed,  J    MED  CHEM  PerspecOve  }  1996              à  Cloning  of  mouse,  rat,  human  FAAHs  (Nature  1996;  PNAS  1997)  }  2010              à  Design,  synthesis  of  ligands  for  FAAH,    MAGL,  ABHD,  DAGL,  

 NAAA,    Lipidomics  irreversible  inhibitors  of  FAAH  (J  Med  Chem,2014)  

•  Cannabinoids  and  pain:  Avenues  for  drug  development  •  THC  +/-­‐  cannabidiol  (dose;  PK/PD)  •  Pain  and  no-­‐pain  contexts  •  In  combinaOon  with  opiates  

(increasing  efficacy  while  reducing  adverse  events)  

•  Effects  on  novel  targets  (GlyR,  TRPs,  etc)  

•  CB1-­‐GPCR  heteromers/Dual  ligand  probes   Ben  Crava(  (P01  DA017259)  

Endocannabinoid  enzyme  structure  &  funcOon  

DBNBR  Fellowships,  Postdocs,  and  Predocs  by  Branch  

0%   10%   20%   30%   40%   50%   60%  

MG  

PN  

BC  

CP  

Total  

F32  

F30,  F31  

   

Percentages  calculated  from    N  Total  Fs=  319        F32s=108        F30,F31=211  

29,  11%  

137,  53%  

92,  36%  

DBNBR  Fellowships:  Predoctoral  and  Postdoctoral  

F30  (MD/PhD  Predoc)  

F31  (Predoc)  

F32  (Postdoc)  

What  types  of  cannabis  research  are  you  currently  supporOng  in  your  porzolio?  

0  

50  

100  

150  

200  

250  

300  

350  

400  

450  

500  

SOmulants   NicoOne   Opiates  &  SedaOves  

Marijuana  

Series1  

DBNBR    Porzolio