IMIDAZOLINE RECEPTORS IN DEPRESSION--BASIC STUDIES

描述(改编自申请者摘要)：本次资助申请 克隆了一个人咪唑烯受体的候选基因 (IR)cDNA和基因。脑干IR被认为在 可乐定对血压的中枢神经元调节，但 IR在其他脑区的可能作用目前尚不清楚 调查。调查员的实验室已经证明 血小板IR放射性配基结合的持续和强劲的升高 对抑郁症患者的五项早期研究，随后是正常化 早期地塞帕明慢性治疗后放射性配基结合的研究 或者氟西汀。调查人员和其他调查人员还观察到 抑郁症自杀者脑组织IR的变化。因此，它 有兴趣确定IR的信号机制和方式 其中IR正常调节，或可能在 抑郁症。建议进行以下研究，以确定 一个克隆的类IR基因：a)第一个目的是确定 研究人员的IR样cDNA编码了药理特性 预期为IR，咪唑啉受体的亚型。初步 转染数据表明，表达的蛋白具有 对IR1和IR2配体有很高的亲和力。B)测试调查员的 IR与选择性磷脂酰胆碱偶联的假设 磷脂酶C(PC-PLC)信号转导途径，它将是 已确定转染的类IR CDN是否会表达配体特异性 耦合到PC-PLC和其他第二信使通路。C)至 确定脑IR的区域化(并测试是否存在 内源性IR候选神经递质--胍丁胺具有类似的 在大鼠和人中的分布)，类IR的区域分布 MRNA也将通过原位杂交进行测定。D)最终目标是 这笔拨款将用于识别可能的调控DNA序列 人和大鼠IR基因的上游基因启动子区域。这些 研究将阐明红外ANIT信号的分子性质 转导通路。这项基本拨款按主题链接到一个 临床补助金(Halaris，PI)，也已提交申请 对价。这项临床拨款将探索大脑IR1 抑郁症患者脑内蛋白质、IR1mRNA和胍丁胺水平升高 自杀者，咪唑啉受体是否是迟钝增长的基础 抑郁症患者对可乐定的激素反应，以及 无论是血小板IR1水平和/或血浆胍丁胺浓度 对抑郁症的严重程度很敏感。来自临床的发现 格兰特将在这些研究的背景下得到最好的理解 基本赠款，反之亦然。

DESCRIPTION (Adapted from applicant's abstract): This grant application presents the cloning of a candidate for the human imidiazolene receptor (IR) cDNA and gene. The brainstem IR has been thought to function in the central neuronal modulation of blood pressure by clonidine, but the probable role of IR in other brain region is currently under investigation. The investigator's laboratory has demonstrated consistent and robust elevations in platelet IR radioligand binding in five earlier studies of depressed patients, followed by a normalization of radioligand binding after chronic treatments with earlier desipramine or fluoxetine. The investigator and other investigators also observed alterations in IR in depressed suicide victims brain tissue. Hence it is of interest to identify the signaling mechanisms of IR and the manner in which IR are normally regulated, or possibly dysregulated in depression. The following studies are proposed in order to characterize a cloned IR-like cDNA: a)The first aim is to establish whether the investigator's IR- like cDNA encodes the pharmacological properties expected of the IR, subtype of imidzoline receptors. Preliminary transfection data have indicated that the expressed protein possesses high affinity for IR1>IR2 ligands. b) To test the investigator's hypothesis that IR are coupled to a phosphatidylcholine-selective phospholipase C (PC-PLC) signal transduction pathway, it will be determined whether transfected IR-like cDN will express ligand-specific coupling to the PC-PLC, and other second messenger pathways. c) To determine the regionalization of brain IR (and to test whether an endogenous IR candidate neurotransmitter, agmatine, shares a similar distribution in rats and humans), the regional distribution of IR-like mRNA will also be determined by situ hybridization. d) A final aim of this grant will be to identify possible regulatory DNA sequences in the upstream gene promoter region of the human and rat IR gene. These studies will clarify the molecular nature of the IR anit's signal transduction pathways. This basic grant is thematically linked to a clinical grant (Halaris, PI) which has also been submitted for consideration. The clinical grant will explore whether brain IR1 protein, IR1 mRNA and agmatine are elevated in brains of depressed suicide victims, whether imidazoline receptors underlie a blunted growth hormone response to clonidine as observed in depressed patients, and whether platelet IR1 levels and/or plasma agmatine concentrations are sensitive to the severity of depression. The findings from the clinical grant will best be understood within the context of these studies in the basic grant, and vice versa.