Interactions between Imidazoline and Insulin Receptors

描述(由申请人提供)： 这份R03申请来自一家代表性不足的少数族裔研究人员，它响应了PAR-02-032，并解决了NIDDK研究的一个新重点--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”。我对咪唑啉受体对用于治疗高血压的激动剂的反应进行了博士后研究，这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型有关。代谢综合征X影响着7500万美国人，在全球范围内是一种日益严重的流行病。药物治疗的选择有限，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巨大的潜力。莫索尼定是一种在欧洲已知的降压药，在动物实验中可以改善高胰岛素血症和低脂，同时降低胰岛素抵抗和改善人类的葡萄糖处理率。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。我的总体假设是，咪唑啉受体激动剂通过使胰岛素受体底物和蛋白激酶B磷酸化来增强胰岛素的作用。利用蛋白质印迹、芯片、分子和药理学方法，三个特定的目标将关键验证这一假说：[1]咪唑啉受体与其他亚型的PKC以及JAK/STAT通路是否相连[2]咪唑啉受体与胰岛素受体底物蛋白(IRS1-4)偶联，[3]咪唑啉受体的激活通过蛋白激酶B和磷脂酰肌醇-3-激酶途径与葡萄糖摄取增加偶联。建立咪唑啉和胰岛素受体通路之间的联系表明咪唑啉类药物是治疗糖尿病合并高血压和降低胰岛素抵抗的候选药物。这一新知识将刺激这些药物的进一步发展。

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.