Secondary Research Project: Genetics

二级研究项目：遗传学

• 批准号: 7892512
• 负责人: Joseph F. Cubells
• 金额: $ 14.42万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892512
• 关键词: Adrenal Glands; Aftercare; Antidepressive Agents; Biochemical; Biological Assay; Biological Markers; Blood; Candidate Disease Gene; Chaperone Gene; Clinical; Clinical assessments; Data; Databases; Development; Dexamethasone; Disease Progression; Early identification; Endocrine; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genotype; Glucocorticoid Receptor; Goals; Haplotypes; Hyperactive behavior; Hypothalamic structure; Image; In Vitro; Investigation; Major Depressive Disorder; Measurement; Measures; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Operative Surgical Procedures; Patients; Peripheral; Phenotype; Pituitary Gland; Population; Procedures; Research Methodology; Research Project Grants; Structure; Testing; Treatment outcome; Variant; depressed; hypothalamic-pituitary-adrenal axis; in vivo; mRNA Expression; monocyte; novel; peripheral blood; predictive modeling; receptor; receptor function; receptor sensitivity; response; response marker; treatment response

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.

该项目的总体目标是确定下丘脑-垂体-肾上腺 (HPA) 轴相关的 参数作为疾病进展和治疗反应的潜在预测因子和/或生物标志物 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， 更具体地说，与糖皮质激素受体（GR）功能有关。这些参数可能包括基因型或 GR 相关位点的单倍型、GR 伴侣基因表达的差异、GR 的测量 体内和体外功能，或这些的某种组合。一旦我们的基因研究确定 治疗反应的假定预测因素，它们将与神经影像、转运蛋白占用的数据相结合 研究、临床评估和其他数据纳入总体反应模型 将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 轴相关的之间的关系 标记物，在基因型、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 受体调节基因的基因水平上的序列变异如何关联 多个时间点从患者体内分离的单核细胞中的 mRNA 表达，以及糖皮质激素 受体功能在体外（即单核细胞）和体内（使用组合 地塞米松抑制/CRH 刺激 (DEX-CRH) 试验）。 整合多个层次的分析可能有助于确定 HPAaxis 的遗传和分子机制 抗抑郁治疗的失调及其正常化，从而表明 抗抑郁治疗反应或疾病进展的特定预测因子。的阐明 伴随成功的 HPA 轴过度活跃的分子机制 抗抑郁治疗也可能是开发新型抗抑郁药的重要一步。 该项目将通过协调所有方面与运营和临床评估核心密切互动 必要的抽血和内分泌挑战测试，并通过整合遗传基因的共享数据库 和表型数据，研究方法核心，通过对所有候选基因的多态性进行基因分型 与该项目相关并提供有关其特定人群单倍型结构的详细信息， 和特殊科学程序核心，通过生成多级 HPA 轴相关数据以包含在 治疗结果的总体预测模型。