5-HT2A RECEPTOR IN DEPRESSION: MOLECULAR MECHANISMS

5-HT2A 受体抑郁：分子机制

• 批准号: 6199105
• 负责人: Steven J Garlow
• 金额: $ 26.79万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-15 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6199105
• 关键词: disease /disorder model; genetic mapping; genetic promoter element; genetically modified animals; genotype; glucocorticoids; immunoregulation; laboratory mouse; major depression; molecular pathology; pathologic process; phenotype; quantitative trait loci; receptor expression; reporter genes; serotonin receptor

DESCRIPTION: (Adapted from applicant's abstract) Dysfunction of the serotonergic system is considered to play a central role in the genesis of major depression and schizophrenia. In particular, the 5-HT2A receptor has been implicated in the pathophysiology of depression and schizophrenia and as the site of action of various psychotherapeutic agents. The most important and consistent finding of serotonergic dysfunction in major depression is increased B of the S-HT2A receptor. This has been documented in the CNS and in the periphery of depressives. The molecular mechanisms that underlie the changes in receptor expression in depression are not understood. The objectives of this proposal are to identify and characterize the factors that regulate the expression of the 5-HT2A receptor, and relate those mechanisms to the pathophysiology of depression. Three Specific Aims are proposed that examine the different levels of regulation of the receptor. The goal of the first Specific Aim is to map genes that control the level of expression of the 5-HT2A receptor in the brain, and begin to identify those genes. This will be accomplished through genetic analysis of Recombinant Inbred (RI) strains of mice, with QTL analysis. The final step in the genetic analysis will be to identify the relevant genes. The experiments in this Aim will also test whether the same genes control the expression of the receptor throughout the body. The goal of the second Specific Aim is to identify critical elements in the promoter for the S-HT2A gene that direct cell specific expression of the receptor. A series of transgenic animals will be produced that have different versions of the S-HT2A promoter driving expression of a reporter gene. The hypothesis tested is that the expression of the receptor is controlled by the interplay of positive and negative response elements in the receptor promoter. The goal of the third Specific Aim is to determine whether a number of growth factors control the expression of the S-HT2A receptor. These experiments will use a number of cells in culture that express the S-HT2A receptor. These cells have been derived from both the CNS and peripheral tissues. The factors that will be tested include glucocorticoids, and a series of immune regulators. These factors are known to be altered in depression and can exert powerful regulatory influences on the expression of a number of genes. As the factors are characterized in the in vitro systems, their relevance to the regulation of the S-HT2A receptor in the brain will be tested in experimental animals.

描述：（改编自申请人的摘要）功能障碍 血清素能系统被认为在疾病的发生中发挥着核心作用 重度抑郁症和精神分裂症。特别是 5-HT2A 受体 与抑郁症和精神分裂症的病理生理学有关 各种精神治疗药物的作用部位。最重要的和 重度抑郁症中血清素功能障碍的一致性发现增加 S-HT2A 受体 B。这已在 CNS 和 抑郁症患者的外围。引起这些变化的分子机制 抑郁症中的受体表达尚不清楚。本次活动的目标 建议的目的是确定和描述调节因素 5-HT2A 受体的表达，并将这些机制与 抑郁症的病理生理学。提出了三个具体目标来审查 受体的不同调节水平。第一个目标 具体目标是绘制控制 5-HT2A 表达水平的基因图谱 大脑中的受体，并开始识别这些基因。这将是 通过对重组近交系 (RI) 品系进行遗传分析来完成 小鼠，进行QTL分析。遗传分析的最后一步是 识别相关基因。该目标中的实验还将测试是否 相同的基因控制着全身受体的表达。这 第二个具体目标的目标是确定 S-HT2A 基因的启动子，指导细胞特异性表达 受体。将产生一系列具有不同特征的转基因动物 驱动报告基因表达的 S-HT2A 启动子版本。这 所检验的假设是受体的表达受 受体启动子中正响应元件和负响应元件的相互作用。 第三个具体目标的目标是确定一些增长是否 控制 S-HT2A 受体表达的因素。这些实验将 使用一些表达 S-HT2A 受体的培养细胞。这些细胞 均来源于中枢神经系统和周围组织。那些因素 将测试的包括糖皮质激素和一系列免疫调节剂。 众所周知，这些因素在抑郁症中会发生改变，并且可以发挥强大的作用 对许多基因表达的调节影响。由于因素 在体外系统中具有特征，它们与调节的相关性 大脑中的S-HT2A受体将在实验动物身上进行测试。