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: 6808734
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808734
• 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民族研究者的R 03申请回应了PAR-02-032，并解决了一个新的NIDDK研究优先事项-了解胰岛素受体和其他可能影响葡萄糖代谢的受体之间的“串扰”。我的博士后研究咪唑啉受体功能对用于治疗高血压的激动剂的反应，使我能够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型糖尿病和代谢综合征X有关。代谢综合征X影响着7500万美国人，并且在全球范围内日益流行。药物治疗选择有限，迫切需要新的药物。咪唑啉受体激动剂（利美尼定，莫索尼定）为X综合征和2型糖尿病的治疗提供了重要的潜力。莫索尼定是欧洲已知的抗高血压药物，在动物研究中可改善高胰岛素血症和降低血脂，同时在人体中可降低胰岛素抵抗和改善葡萄糖处置率。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B的磷酸化增强胰岛素作用。使用蛋白质印迹，微阵列，分子和药理学方法，三个具体的目标将通过确定是否严格测试这一假设：[1]咪唑啉受体与PKC的其他亚型以及JAK/STAT途径偶联[2]咪唑啉受体与胰岛素受体底物蛋白（IRS 1 -4）偶联，[3]咪唑啉受体活化与通过蛋白激酶B和磷脂酰肌醇-3-激酶途径增加葡萄糖摄取有关。建立咪唑啉和胰岛素受体途径之间的联系表明咪唑啉药物是治疗糖尿病伴高血压和降低胰岛素抵抗的候选药物。这些新知识将促进这些药物的进一步开发。