Secondary Research Project: Genetics

本项目的总体目标是确定下丘脑-垂体-肾上腺（HPA）轴相关的 作为疾病进展和对治疗的反应的潜在预测因子和/或生物标志物的参数， 初治患者的重度抑郁症我们将开发与HPA轴相关的候选参数， 更具体地，涉及糖皮质激素受体（GR）功能。这些参数可以包括基因型或 GR相关基因座的单倍型，GR伴侣基因表达的差异，GR的测量 在体内和体外发挥作用，或它们的某种组合。一旦我们的基因调查确定 作为治疗反应的假定预测因子，它们将与来自神经成像、转运蛋白和免疫组化的数据相结合。 纳入总体缓解模型的研究、临床评估和其他数据 在特别科学程序核心中开发的预测因子。 该项目的具体目标包括检查HPA轴相关的神经元之间的关系。 在基因型、mRNA表达、生物化学和系统水平上测量的标记物。更具体 我们将研究GR受体调节基因在遗传水平上的序列变异如何与 在多个时间点从患者分离的单核细胞中的mRNA表达， 体外测定的受体功能（即，在单核细胞中）以及在体内（使用组合的 地塞米松抑制/CRH刺激（DEX-CRH）试验）。 整合多层次的分析可能有助于确定HPA轴的遗传和分子机制 调节异常及其正常化，从而表明 抗抑郁治疗反应或疾病进展的特异性预测因子。阐明 HPA轴活动过度正常化的分子机制， 抗抑郁治疗也可能是开发新型抗抑郁药的重要一步。 该项目将与运营和临床评估核心密切互动，协调所有 必要的抽血和内分泌挑战测试，并通过共享数据库整合遗传 和表型数据，研究方法核心是通过对所有候选基因的多态性进行基因分型 与本项目相关，并提供有关其群体特异性单倍型结构的详细信息， 和特别科学程序核心，生成多层次HPA轴相关数据， 治疗结果的总体预测模型。

The overarching goal of this project is to identify hypothalamic-pituitary-adrenal (HPA)-axis-related parameters as potential predictors and/or biomarkers of disease progression and response to treatment for major 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 or haplotypes at GR-related loci, differences in expression of GR chaperone genes, measurements of GR function in vivo and in vitro, or some combination of these. Once our genetic investigations have identified putative predictors of treatment response, they will be integrated with data from neuro-imaging, transporteroccupancy studies, clinical assessments and other data for inclusion in an overall model of response predictors to be developed in the Special Scientific Procedures Core. The specific aims of this project include examination of relationships among HPA-axis-associated markers, measured at the genotypic, mRNA-expression, biochemical and systemic levels. More specifically we will investigate how sequence variation at the genetic level in GR receptor- regulating genes associate with mRNA expression in monocytes isolated from patients at multiple timepoints, and to glucocorticoid receptor function measured in vitro (i.e., in monocytes) as well as in vivo (using the combined dexamethasone suppression/CRH stimulation (DEX-CRH) test). Integrating multiple levels of analysis may help to identify genetic and molecular mechanisms for HPAaxis dysregulation and its normalization in response to anti-depressant treatment, thereby suggesting specific predictors for response to antidepressant treatments or disease progression. The elucidation of molecular mechanisms for the normalization of HPA-axis hyperactivity that accompanies successful antidepressant 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 all necessary blood draws and endocrine challenge tests and through a shared database integrating genetic and phenotypic data, the Research Methods Core by genotyping polymorphisms in all candidate genes relevant 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 in the overall predictive model for treatment outcome.