The overarching goal of this project is to identify hypothalamic-pituitary-adrenal (HPA)-axis-relatedparameters as potential predictors and/or biomarkers of disease progression and response to treatment formajor depression in treatment-naTve patients. We will develop candidate parameters related to the HPA-axis,and more specifically, to glucocorticoid receptor (GR) function. Those parameters may include genotypes orhaplotypes at GR-related loci, differences in expression of GR chaperone genes, measurements of GRfunction in vivo and in vitro, or some combination of these. Once our genetic investigations have identifiedputative predictors of treatment response, they will be integrated with data from neuro-imaging, transporteroccupancystudies, clinical assessments and other data for inclusion in an overall model of responsepredictors to be developed in the Special Scientific Procedures Core.
The specific aims of this project include examination of relationships among HPA-axis-associatedmarkers, measured at the genotypic, mRNA-expression, biochemical and systemic levels. More specificallywe will investigate how sequence variation at the genetic level in GR receptor- regulating genes associatewith mRNA expression in monocytes isolated from patients at multiple timepoints, and to glucocorticoidreceptor function measured in vitro (i.e., in monocytes) as well as in vivo (using the combineddexamethasone suppression/CRH stimulation (DEX-CRH) test).Integrating multiple levels of analysis may help to identify genetic and molecular mechanisms for HPAaxisdysregulation and its normalization in response to anti-depressant treatment, thereby suggestingspecific predictors for response to antidepressant treatments or disease progression. The elucidation ofmolecular mechanisms for the normalization of HPA-axis hyperactivity that accompanies successfulantidepressant treatment may also be an important step in the development of novel antidepressants.This project will interact closely with the Operations and Clinical Assessment Core by coordinating allnecessary blood draws and endocrine challenge tests and through a shared database integrating geneticand phenotypic data, the Research Methods Core by genotyping polymorphisms in all candidate genesrelevant for this project and providing detailed information on their population-specific haplotypic structure,and the Special Scientific Procedures Core by generating multi-level HPA-axis related data for inclusion inthe overall predictive model for treatment outcome.
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