PET 1 ETS FACTOR IN THE MAMMALIAN 5 HT SYSTEM

描述(摘自申请者的摘要)：这份申请提出了一个独特的 以哺乳动物的发育和功能为目标的研究途径 5-羟色胺神经递质系统这项研究是基于我们对一种 新的Ets结构域转录因子Pet-1，其表达准确地标记 5-羟色胺神经元在5-羟色胺出现之前出现在后脑，在5-羟色胺神经元出现之前 开始迁移到成年的中脑/后脑位置。发现了 哺乳动物5-羟色胺特异表达的转录因子 这个系统是史无前例的。它的5-羟色胺能特异性表达模式一起 在人类和小鼠基因中存在一个Pet-1 DNA结合位点，这 在很大程度上决定了5-HI神经元的分化表型 Pet-1是决定成为5-羟色胺神经元的关键决定因素。这个 本申请中描述的实验旨在验证这一假设 并利用Pet-1的挑衅表达模式来控制 异源基因以5-羟色胺能特异的方式表达。建议数 目的是：1)研究Pet-1的替代形式和表达 5-羟色胺系统中的其他ETS因子。2)鉴定宠物基因组DNA片段 能够控制5-羟色胺能特异性基因的表达。3)调查 Pet-1与5-羟色胺转运体的转录相互作用 (5-HTT)、5-HT1a受体和色氨酸羟解酶(TPH)基因。4)创建 PET-1功能丧失小鼠并测定其表型。的功能 中枢5-羟色胺系统在许多精神障碍中异常，因此 系统是几种高效药理学药物的靶标 是用来治疗这些疾病的。完成以下工作所取得的资料 拟议的目标可能会对我们的基本目标产生重大影响 对5-羟色胺系统的理解，并可能在未来导致创建 涉及5-羟色胺系统的新型精神障碍动物模型。

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.