PET 1 ETS FACTOR IN THE MAMMALIAN 5 HT SYSTEM

哺乳动物 5 HT 系统中的 PET 1 ETS 因子

• 批准号: 6825754
• 负责人: EVAN S DENERIS
• 金额: $ 30.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-10 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825754
• 关键词: developmental genetics; developmental neurobiology; gene induction /repression; genetically modified animals; laboratory mouse; neurogenetics; pons; protein isoforms; serotonin; serotonin receptor; serotonin transporter; transcription factor; tryptophan 5 monooxygenase

DESCRIPTION (From applicant's abstract): This application proposes a unique avenue of research aimed at the development and function of the mammalian serotonin neurotransmitter system. The research is based on our discovery of a novel ETS domain transcription factor, Pet-1, whose expression precisely marks 5-HT neurons before 5-HT appears in the hindbrain and before 5-HT neurons have begun to migrate to their adult midbrain/hindbrain positions. The discovery of a transcription fact that is specifically expressed in the mammalian 5-HT system is unprecedented. It serotonergic-specific expression pattern together with the presence of a Pet-1 DNA binding sites in human and mouse genes, which in large part defines the differentiated phenotype of 5-HI neurons, suggest that Pet-1 is a key determinant in the decision to become a 5-HT neuron. The experiments described in this application are aimed at testing this hypothesis and to exploit the provocative expression pattern of Pet-1 to control heterologous gene expression in a serotonergic-specific manner. The proposed aims are: 1) Investigate expression of Pet-1 alternative forms and expression of other ETS factors in the 5-HT system. 2) Identify a Pet genomic DNA fragment capable of controlling serotonergic-specific gene expression. 3) Investigate the transcriptional interaction of Pet-1 with the serotonin transporter (5-HTT), 5 HT1a receptor and tryptophan hydroxlase (TPH) genes. 4) Create a Pet-1 loss of function mouse and determine its phenotype. The function of the central 5-HT system is abnormal in numerous psychiatric disorders and thus this system is the target of several highly effective pharmacological agents that are used to treat these disorders. The information gained from completion of the proposed aims is likely to have significant impact on our basic understanding of the 5-HT system and may lead in the future to the creation of novel animal models for psychiatric disorders involving the 5-HT system.

描述（来自申请人的摘要）：该申请提出了一种独特的 旨在研究哺乳动物的发育和功能的途径 血清素神经递质系统。这项研究基于我们的发现 新型ETS结构域转录因子Pet-1，其表达精确标记 5-HT 神经元在 5-HT 出现在后脑之前以及在 5-HT 神经元出现之前 开始迁移到成年中脑/后脑位置。的发现 在哺乳动物 5-HT 中特异性表达的转录因子 系统是前所未有的。它与血清素能特异性表达模式一起 人类和小鼠基因中存在 Pet-1 DNA 结合位点， 在很大程度上定义了 5-HI 神经元的分化表型，表明 Pet-1 是决定成为 5-HT 神经元的关键决定因素。这 本申请中描述的实验旨在检验该假设 并利用 Pet-1 的挑衅性表达模式来控制 异源基因以血清素能特异性方式表达。拟议的 目标是： 1) 研究 Pet-1 替代形式的表达和表达 5-HT 系统中的其他 ETS 因素。 2) 鉴定宠物基因组 DNA 片段 能够控制血清素能特异性基因表达。 3）调查 Pet-1 与血清素转运蛋白的转录相互作用 (5-HTT)、5 HT1a 受体和色氨酸羟化酶 (TPH) 基因。 4）创建一个 Pet-1丧失功能小鼠并测定其表型。的功能 中枢 5-HT 系统在许多精神疾病中出现异常，因此 系统是几种高效药物的目标 用于治疗这些疾病。完成后获得的信息 拟议的目标可能会对我们的基本目标产生重大影响 了解 5-HT 系统并可能在未来导致创建 涉及 5-HT 系统的精神疾病的新型动物模型。