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Elisabeth Binder

Elisabeth Binder. MPI Psychiatry Munich binder@mpipsykl.mpg.de 089-30622-301. ERC starting grant. 2007 – RG leader MPI Psychiatry 2008 -1. application/panel LS5 - neuroscience 'Genetic determinants of stress hormone response and unipolar depression ' Upload error

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Elisabeth Binder

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  1. Elisabeth Binder MPI Psychiatry Munich binder@mpipsykl.mpg.de 089-30622-301

  2. ERC starting grant • 2007 – RG leader MPI Psychiatry • 2008 -1. application/panel LS5 - neuroscience • 'Genetic determinants of stress hormone response and unipolar depression' • Upload error • The binding statement from the Host Institution was missing. • 2009 – 2. application • same title, only small changes to 2008 • >2 points each for research project and PI each • No interview • Too „hypothesis generating“

  3. ERC starting grant • 2010 – 3. application • Gene x environment interactions in affective disorders – elucidating molecular mechanisms • Except for 1 aim, all different • Focus on one central hypothesis and follow-up on several levels • Invited for interview and selected for funding

  4. Elisabeth Binder ERC Starting GrantGene x environment interactions in affective disorders –elucidating molecular mechanismsGxE molmech

  5. Overview curriculum vitae Medical • MD (MUW/ULB Vienna/Brussels) • Psychiatry/Neuroendocrinology (MPI Psychiatry Munich) Neuroscience • PhD (Emory University Atlanta/USA) Human Genetics • Post-doctoral work (MPI Psychiatry/TUM Munich) Currently • group leader (W2) at Max-Planck Institute of Psychiatry • Assistant Professor Emory University School of Medicine • Triple education important for sucessful translational research • Recent achievements Ressler…Binder, May. 2011 Nature – new gene/biomarker for post traumatic stress disorder (PTSD) Kohli…Binder. 2011 Neuron – new candidate gene for unipolar depression Metha…Binder. 2011 Archives of General Psychiatry – new biological subgroups of PTSD

  6. Stress/trauma-related psychiatric disorders • High life time prevalence • unipolar depression 10-20% • post traumatic stress disorder (PTSD) 3-10% • Pathophysiology? • Genes and Environment • Treatments insufficient • High burden on individual and society Understanding of risk and resilience factors for stress-related psychiatric disoders New therapeutic approaches

  7. GR GR Ultrashort negative feedback on GR sensitivity hsp90 FKBP5 FKBP5 cortisol GR GR hsp90 FKBP4 AAAAA dynein GR GR hsp90 5‘ 3‘ GRE GRE GRE GRE GRE Glucocorticoid response elements in FKBP5 FKBP5 and stress-related disorders FKBP5 – a regulator of glucocorticoid receptor function

  8. rs1360780 CC rs1360780 CT/TT rs1360780 CC 40 CT 35 FKBP5 levels TT 30 25 PTSD symptom severity 20 1 type of abuse 2 types of abuse no abuse 15 baseline stimulation feedback 10 5 Cortisol levels 0 Polymorphisms in FKBP5 locus • alter FKBP5/GR feedback loop (Binder et al., Nature Genetics 2004) • Alter GR sensitivity and cortisol response after stress (Binder et al,. JAMA 2008, Ising et al,. 2008) • interact with early trauma to predict psychiatric symptoms (Binder et al,. JAMA 2008, Xie et al,. 2010) • define inherent risk and resilience to stress/trauma (Binder Psychoneuroend. 2009) Psychiatric effects Molecular and endocrine effects

  9. Molecular mechanisms of stress x gene interactions? M M M Genetic polymorphisms Environment Stress related disorders DNA methylation CmetG FKBP5 risk allele + early trauma = prolonged GR activation = DNA demethlyation

  10. Transcription start site with CpG island Intron 7 GRE Intron 5 GRE Intron 2 GRE ** 100 no trauma + FKBP5 protective no trauma + FKBP5 risk 90 ** 80 Trauma + FKBP5 protective ** 70 Trauma + FKBP5 risk 60 % DNA methylation 50 40 30 20 10 0 CG intron 2 Pos2 CG intron 7 Pos2 CG intron 7 Pos3 Allele-specific DNA demethylation in FKBP5 locus may mediate GxE • 10 CGs in GREs of FKBP5 are methylated – 50-90% • CGs are de-methylated in risk allele carriers with trauma exposure • Functionality of GRE methylation supported by reporter gene assays

  11. Clinical research Cell lines High throughput genomics Animal models Translational approach – GxE molmech

  12. Aims of ERC proposal • Further characterization of FKBP5 GRE methylation in human tissue • FKBP5 methylation and GR/FKBP5 feedback FKBP5 methylation in peripheral blood and molecular and systemic/endocrine measures in vivo • Allele-specific demethylation – GR activation or methyl CpG-binding domain (MBD) proteins? Effects of prolonged GR stimulation and genotype on FKBP5 methylation and MBDs (MeCP2) in cell lines

  13. Aims of ERC proposal • Do rare variants in FKBP5 contribute to GxE interactions? Next generation sequencing in 400 traumatized individuals Genotype variants in large sample (N = 5000) for GxE interactions Function of FKBP5 – transgenic animal models Function of FKBP5 – transgenic animal models

  14. 25 control chronic social stress 20 * 15 corticosterone ng/ml 10 5 0 TT GT GG rs13482937 in fkbp5 Aims of ERC proposal • Can FKBP5 x early trauma interaction be modeled on molecular level in mice? Mouse fkbp5 SNPs + chronic social stress = longterm stress hormone hyperactivity molecular correlates of FKBP5 x stress interaction in blood and brain More face validity than genetic or environmental manipulations alone

  15. Aims of ERC proposal • Can analogue mechanisms be detected for other GR-responsive genes? • Expression quantitative trait loci (eQTLs) for GR-stimulated gene expression in peripheral blood • top eQTLs in GxE study of 5000 individuals for association with psychiatric disorders • Allele-specific methylation of candidate genes

  16. Team and support RG M. Schmidt NGS core Methods Data analysis On-going recruitment On-going recruitment Infrastructure Grady trauma project (NIMH) Grady trauma project (NIMH) RG B. Müller-Myhsok RG B. Müller-Myhsok Aim 4 eQTLs Aim 2 FKBP5 sequencing Aim 1 FKBP5 methylation Aim 3 Animal model Postdoc 2 Statistics Technician 1 PhD student 1 Postdoc 1 MD/Molecular biology Torsten Klengel PhD student 2 Technician 1 Postdoc 2 Statistics Technician 1

  17. Innovation GxE molmech First molecular mechanism for GxE in psychiatry Better understanding of pathophysiology of stress-related psychiatric disorders Treatments based on causal mechanisms

  18. Budget • 1.045.100 € direct costs • 700.000 € personnel • 2 postdocs 30 months each • 2 PhD students – 36 months each • 1 technician – 60 months • 345.100 € supplies and others • DNA methylation and ChIP – 75.000 € • Genotyping – 60.000 € for 300 Illumina arrays – 20.000 € Sequenom – • Gene expression - 35.000 € for Illumina arrays – 9.000 € for RT-PCR • Next generation sequencing – 24.600 € • General lab supplies, travel, reimbursements, licences

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