Secondary Research Project: Genetics

该项目的首要目标是确定与下丘脑-垂体-肾上腺(HPA)轴相关的 作为疾病进展和治疗反应的潜在预测和/或生物标志物的参数 治疗中的重度抑郁症-NATVE患者。我们将开发与HPA轴相关的候选参数， 更具体地说，与糖皮质激素受体(GR)功能有关。这些参数可能包括基因类型或 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，或这些功能的某种组合。一旦我们的基因研究确定 作为治疗反应的假定预测指标，它们将与神经成像、交通工具占用等数据相结合 纳入总体反应模式的研究、临床评估和其他数据 将在特别科学程序核心中开发预报器。 该项目的具体目标包括审查与HPA轴相关的 标记，在基因类型、mRNA表达、生化和系统水平上进行测量。更具体地说 我们将研究GR受体调节基因在遗传水平上的序列变异是如何关联的 在多个时间点分离的患者单核细胞中有mRNA表达，并与糖皮质激素有关 在体外(即，在单核细胞中)以及在体内(使用联合 地塞米松抑制/CRH刺激(DEX-CRH)试验)。 综合多个层次的分析可能有助于确定HPA轴的遗传和分子机制 抗抑郁药物治疗后的调节失调及其正常化，从而提示 抗抑郁药物治疗反应或疾病进展的特定预测因子。阐明了 伴随成功的HPA轴过度活动正常化的分子机制 抗抑郁治疗也可能是开发新型抗抑郁药物的重要一步。 该项目将与业务和临床评估核心密切互动，协调 必要的抽血和内分泌挑战测试，并通过一个共享的数据库整合基因 和表型数据，研究方法的核心是对所有候选基因的多态进行基因分型 与该项目相关，并提供其特定于种群的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，供纳入 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.