IMIDAZOLINE RECEPTORS IN DEPRESSION--BASIC STUDIES

抑郁症中的咪唑啉受体——基础研究

• 批准号: 2890501
• 负责人: JOHN E PILETZ
• 金额: $ 22.52万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2890501
• 关键词: biological signal transduction; cell line; complementary DNA; depression; genetic promoter element; human genetic material tag; human tissue; imidazole; in situ hybridization; laboratory rat; lipid metabolism; molecular cloning; phosphatidylcholines; phospholipase C; postmortem; receptor binding; receptor expression; regulatory gene; transfection

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.

描述（改编自申请人的摘要）：本补助金申请 提出了人类咪唑啉受体候选者的克隆 (IR) cDNA 和基因。 脑干 IR 被认为具有以下功能： 可乐定对血压的中枢神经元调节作用 IR 在其他大脑区域中的可能作用目前正在研究中 调查。 研究人员的实验室已经证明 血小板 IR 放射性配体结合持续且强劲的升高 五项针对抑郁症患者的早期研究，随后进行了正常化 早期地昔帕明长期治疗后放射性配体结合的影响 或氟西汀。 调查员和其他调查员还观察到 抑郁症自杀受害者脑组织中 IR 的变化。 因此它 感兴趣的是确定 IR 的信号传导机制和方式 其中IR通常受到调节，或者可能在以下情况下失调 沮丧。 为了描述特征，提出以下研究 克隆的 IR 样 cDNA：a)第一个目标是确定是否 研究人员的 IR 样 cDNA 编码药理学特性 IR，咪唑啉受体亚型的预期。 初步的 转染数据表明表达的蛋白质具有 对 IR1>IR2 配体具有高亲和力。 b) 测试研究者的 IR 与磷脂酰胆碱选择性偶联的假设 磷脂酶 C (PC-PLC) 信号转导通路 确定转染的 IR 样 cDN 是否会表达配体特异性 耦合到 PC-PLC 和其他第二信使路径。 c) 至 确定大脑 IR 的区域化（并测试是否 内源性 IR 候选神经递质，胍丁胺，具有相似的特征 大鼠和人类的分布），类IR的区域分布 mRNA 也可通过原位杂交测定。 d) 最终目标 这笔资助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 研究将阐明红外线信号的分子性质 转导途径。 这笔基本拨款的主题与 临床补助金（Halaris，PI）也已提交 考虑。 该临床拨款将探讨大脑 IR1 是否 抑郁症患者大脑中蛋白质、IR1 mRNA 和胍丁胺升高 自杀受害者，咪唑啉受体是否是生长迟缓的原因 在抑郁症患者中观察到的对可乐定的激素反应，以及 血小板 IR1 水平和/或血浆胍丁胺浓度是否 对抑郁症的严重程度敏感。 临床研究结果 赠款将在这些研究的背景下得到最好的理解 基本补助金，反之亦然。