Novel Mechanisms and Targets for Major Depressive Disorder in Astrocytes

DESCRIPTION provided by applicant Astrocytes are increasingly understood to be active players in the etiology and treatment of Major Depressive Disorders MDD or depression and offer a new biological area for development of novel antidepressant drugs The goal of this project is to understand the molecular mechanisms of action of antidepressant drugs on astrocytes The knowledge gained will create opportunities to identify novel targets for discovery of new antidepressant drugs and biomarkers that predict or stratify drug response We have developed an innovative high throughput in vitro platform for genomewide association studies IV GWAS of drug response In this project we will use a genetically diverse population of astrocytes differentiated from mouse embryonic stem cells IV GWAS vastly increases the number of genetic screens over conventional live animal or human GWAS Further the in vitro environment can be tightly controlled which increases statistical power and enables more precise experimental designs We will identify genes that modify phenotypes relevant to depression in astrocytes treated with antidepressant drugs We will test almost all of the antidepressant drugs in current use a set of compounds In Phase I we will pre screen the compounds and phenotypes to identify those exhibiting the largest genetic variability andquot Heritabilityandquot In Phase II we will conduct IV GWAS using cell lines to identify genes that regulate or predict variable response to drug treatment We will validate these findings in both mouse and human astrocytes PUBLIC HEALTH RELEVANCE A more complete understanding of the molecular pathways underlying Major Depressive Disorders MDD is a critical bottleneck in the development of new therapies for depression We want to understand the molecular mechanisms underlying how antidepressant drugs act on astrocytes the most abundant cell type in the brain This will drive discovery of new antidepressant drugs