Interactions between Imidazoline and Insulin Receptors

咪唑啉和胰岛素受体之间的相互作用

• 批准号: 6908211
• 负责人: LINCOLN Paul EDWARDS
• 金额: $ 16.2万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908211
• 关键词: JAK kinase; biological signal transduction; cell line; cytokine receptors; gene expression; glucose transport; hormone regulation /control mechanism; imidazole; immunoprecipitation; insulin receptor; phosphatidylinositol 3 kinase; phosphorylation; polymerase chain reaction; protein isoforms; protein kinase; protein kinase C; receptor binding; receptor coupling; western blottings

DESCRIPTION (provided by applicant): This R03 application from an underrepresented minority investigator responds to PAR-02-032 and addresses a new NIDDK research priority -- understanding the "crosstalk" between the insulin receptor and other receptors that may affect glucose metabolism. My postdoctoral studies on imidazoline receptor function in response to agonists used to treat hypertension have uniquely positioned me to establish an independent research program, relevant not only to cardiovascular disease, but also to type 2 diabetes and Metabolic Syndrome X. Metabolic Syndrome X affects 75 million Americans, and is a growing epidemic worldwide. Pharmacologic treatment options are limited and new agents are urgently needed. Imidazoline receptor agonists (rilmenidine, moxonidine) offer significant potential for the treatment of syndrome X and type 2 diabetes. Moxonidine, a known antihypertensive agent in Europe, ameliorate hyperinsulinemia and lower lipids in animal studies, while reducing insulin resistance and improving glucose disposal rates in humans. Our project goal is to discover the unknown mechanism by which imidazoline receptor agonists exert these beneficial effects. My general hypothesis is that imidazoline receptor agonists enhance insulin action via phosphorylation of insulin receptor substrates and protein kinase B. Using Western blot, microarray, molecular and pharmacologic methods, three specific aims will critically test this hypothesis by determining whether: [1] imidazoline receptors are coupled to additional isoforms of PKC and also JAK/STAT pathways [2] Imidazoline receptors are coupled to insulin receptor substrate proteins (IRS1-4), [3] imidazoline receptor activation is coupled to increased uptake of glucose via the Protein kinase B and phosphatidylinositol-3-kinase pathway. Establishing a link between imidazoline and insulin receptor pathways suggests that imidazoline agents are candidate drugs to treat diabetics with hypertension and reduce insulin resistance. This new knowledge will stimulate further development of these agents.

描述（由申请人提供）： 来自代表性不足的少数群体研究者的R03应用对PAR-02-032做出了反应，并介绍了新的NIDDK研究优先级 - 了解胰岛素受体与其他可能影响葡萄糖代谢的受体之间的“串扰”。我对用于治疗高血压的激动剂的咪唑啉受体功能的博士后研究使我独特地定位了建立一个独立的研究计划，不仅与心血管疾病有关，而且与2型糖尿病和X型糖尿病和代谢综合征X。药理治疗方案有限，迫切需要新的药物。咪唑啉受体激动剂（Rilmenidine，Moxonidine）为综合征X和2型糖尿病的治疗提供了巨大的潜力。在欧洲是已知的降压剂莫克森丁，在动物研究中可以改善高胰岛素血症和较低的脂质，同时降低胰岛素抵抗并改善人类的葡萄糖处置率。我们的项目目标是发现咪唑啉受体激动剂发挥这些有益作用的未知机制。我的一般假设是，咪唑啉受体激动剂通过胰岛素受体底物和蛋白激酶的磷酸化来增强胰岛素作用。使用蛋白质印迹，微阵列，分子和药理学方法，三个特定目标将通过确定cooforon和stepoforn of perofork of peroforgorm and cofork of peroform and cofork of： [2]咪唑啉受体与胰岛素受体底物蛋白（IRS1-4）偶联，[3]咪唑啉受体的激活与通过蛋白激酶B和磷脂酰糖脂醇 - 3- 3-基因酶途径偶联，以增加葡萄糖的摄取。建立咪唑啉和胰岛素受体途径之间的联系表明，咪唑啉剂是治疗高血压并降低胰岛素耐药性的候选药物。这些新知识将刺激这些代理的进一步发展。