IMIDAZOLINE RECEPTORS IN DEPRESSION--BASIC STUDIES

描述（改编自申请人的摘要）：本补助金申请 克隆了人咪唑啉受体的候选基因 (IR)cDNA和基因。 脑干IR被认为在 可乐定对血压的中枢神经调节作用， IR在其他脑区的可能作用目前尚不清楚。 调查 研究人员的实验室已经证明 血小板IR放射性配体结合的一致和稳健升高， 五个早期的抑郁症患者的研究，随后是正常化， 早期地昔帕明慢性治疗后的放射性配体结合 或氟西汀。 调查人员和其他调查人员还观察到， 抑郁自杀者脑组织IR的改变。 因此它 感兴趣的是识别IR的信号传导机制和 其中IR是正常调节或可能失调， 萧条 建议进行以下研究，以表征 克隆的IR样cDNA：a）第一个目的是确定 研究者的IR样cDNA编码了 IR，咪唑啉受体亚型的预期。 初步 转染数据表明，表达的蛋白具有 对IR 1> IR 2配体具有高亲和力。B）测试研究者的 假设IR与磷脂酰胆碱选择性 磷脂酶C（PC-PLC）信号转导通路，它将 确定转染的IR样cDNA是否将表达配体特异性 与PC-PLC和其他第二信使途径偶联。（c） 确定大脑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 分布在大鼠和人类），IR样的区域分布 还将通过原位杂交测定mRNA。（一）最终目标： 这项拨款将用于确定可能的调控DNA序列， 人和大鼠IR基因的上游基因启动子区。 这些 研究将澄清红外线的分子性质的信号 转导途径。 这项基本补助金按主题与一个 临床补助金（Halaris，PI），也已提交给 考虑. 临床拨款将探索大脑IR 1是否 抑郁症患者脑内IR 1蛋白、IR 1 mRNA和胍丁胺水平升高， 自杀受害者，咪唑啉受体是否是生长迟钝的基础， 在抑郁症患者中观察到的对可乐定的激素反应， 血小板IR 1水平和/或血浆胍丁胺浓度是否 对抑郁症的严重程度敏感。 来自临床的发现 在这些研究的背景下， 基本补助金，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.