Mouse Models, KOs, Transgenics, and Gene Expression Monoamine Systems

小鼠模型、KO、转基因和基因表达单胺系统

• 批准号: 7167304
• 负责人: Marc G. Caron
• 金额: $ 35.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167304
• 关键词: amines; antidepressants; behavior test; biological signal transduction; depression; electroconvulsive therapy; gene deletion mutation; genetic polymorphism; genetically modified animals; laboratory mouse; neurotransmitter transport; norepinephrine; pathologic process; serine threonine protein kinase; serotonin; tryptophan

Depression is a psychiatric disorder where disturbance of mood is a prominent feature. Although the etiology of depression is unknown, alterations in serotonergic and noradrenergic function are implicated in the condition. The present Conte Center Grant proposes to examine depression from perspectives of functional imaging, morphometrics, and pharmacological interventions in humans, as well as though mouse genetic, molecular, biochemical, behavioral, and electrophysiological models of depression. The overall objective of the present proposal is to show how the norepinephrine (NE) and serotonin (5-HT) systems are interdependent in the development and amelioration of symptoms of depression, and to reveal novel mechanisms that contribute to the disorder. There are three major Aims. AIM 1: The roles in depression of the NE transporter, 5-HT transporter, and vesicular monoamine transporter 2 will be investigated. Effects of antidepressants on monoamine and metabolite levels in various brain regions will be studied. Molecular fingerprinting of signal transduction pathways will be used to analyze effects of genotype and antidepressant treatment. AIM 2: The role in depression of glycogen synthase kinase-3beta (GSK3b) will be analyzed. Mice will be developed that have GSK3b selectively deleted in the CNS. Animals will be evaluated according to behavioral, neurotransmitter, and signal transduction responses to antidepressants. AIM 3: Mice will be made that bear the same polymorphisms in tryptophan hydroxylase 2 (Tph2) found in human depressed patients. Mutants will be examined according to behavioral, neurotransmitter, and signal transduction responses to antidepressants and electroconvulsive therapy.

抑郁症是一种精神疾病，其中情绪紊乱是一个突出的特征。虽然 抑郁症的病因尚不清楚，血清素能和去甲肾上腺素能功能的改变是 与病情有关。目前的康特中心格兰特建议从以下方面检查抑郁症： 人类功能成像、形态计量学和药理学干预的观点，如 以及小鼠遗传、分子、生化、行为和电生理模型 抑郁症。本提案的总体目标是展示去甲肾上腺素 (NE) 如何 和血清素 (5-HT) 系统在症状的发展和改善方面相互依赖 抑郁症的研究，并揭示导致该疾病的新机制。主要有以下三个 目标。目标 1：NE 转运蛋白、5-HT 转运蛋白和囊泡抑制的作用 将研究单胺转运蛋白 2。抗抑郁药对单胺和 将研究不同大脑区域的代谢水平。信号的分子指纹 转导途径将用于分析基因型和抗抑郁治疗的效果。目的 图2：将分析糖原合成酶激酶3β（GSK3b）抑制中的作用。老鼠将会 开发出在中枢神经系统中选择性删除 GSK3b 的方法。动物将根据以下进行评估 对抗抑郁药的行为、神经递质和信号转导反应。目标 3：小鼠会 具有与人类发现的色氨酸羟化酶 2 (Tph2) 相同的多态性 抑郁症患者。将根据行为、神经递质和信号对突变体进行检查 对抗抑郁药和电惊厥治疗的转导反应。