Novel Pathways of AGE Formation in Diabetes

糖尿病中 AGE 形成的新途径

• 批准号: 6909787
• 负责人: Ram H Nagaraj
• 金额: $ 15.1万
• 依托单位: CASE WESTERN RESERVE 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/6909787
• 关键词: aldehydes; amino group; bioassay; chemical condensation; clinical research; crosslink; diagnosis design /evaluation; enzyme linked immunosorbent assay; glycation; human subject; ketones; laboratory mouse; laboratory rat; noninsulin dependent diabetes mellitus; patient oriented research; technology /technique development

DESCRIPTION (provided by applicant): The Maillard reaction, the reaction of carbonyl compounds with amino group on proteins occurs at an accelerated rate in diabetes. This reaction produces products known as, advanced glycation end products or AGEs that are detrimental to proteins and cell functions. AGEs have been implicated in all major complications of diabetes. Several inhibitors against AGE synthesis have been tested and a few of them have shown promising results in inhibiting diabetic complications. However, these inhibitors do not appear to be highly specific and may not inhibit intracellular AGEs. In order to develop more specific and potent inhibitors, a thorough knowledge of AGE chemistry is essential. Recently, a new pathway for AGE synthesis has been uncovered. In this pathway, the Amadori products, the initial condensation products of the Maillard reaction undergo spontaneous long-range carbonyl shift to produce protein-bound dideoxyosones. The dideoxyosones can potentially produce significant amounts of AGEs in proteins. Such AGEs may include lysine-arginine and lysine-lysine cross linking structures. In this proposal, we plan to first establish occurrence of dideoxyosone-mediated AGE synthesis in vivo using a novel immunological method and then deduce chemical structure of major AGE specifically arising from dideoxyosone, develop methods for their detection in tissues, assess importance of this pathway for AGE synthesis in diabetes. Our study is expected to provide novel insights into AGE formation in diabetes and may lead to new pharmacological agents to prevent AGE formation and complications in diabetes.

描述（由申请人提供）：Maillard反应，羰基化合物与氨基蛋白的反应在糖尿病中以加速速率发生。该反应产生的产品称为高级糖基化终产物或对蛋白质和细胞功能有害的年龄。年龄与糖尿病的所有主要并发症有关。已经测试了一些针对年龄合成的抑制剂，其中一些抑制剂在抑制糖尿病并发症方面显示出令人鼓舞的结果。但是，这些抑制剂似乎没有高度特异性，并且可能不会抑制细胞内年龄。为了开发更具体和有效的抑制剂，对年龄化学的透彻知识至关重要。最近，已经发现了一种新的年龄合成途径。在这一途径中，Amadori产品，Maillard反应的初始冷凝产物经历了自发的远程羰基移位，以产生结合蛋白质的二氧蛋白酶。甲氧基州可能会在蛋白质中产生大量年龄。这样的年龄可能包括赖氨酸 - 精氨酸和赖氨酸 - 赖氨酸交叉连接结构。在该提案中，我们计划首先使用一种新型的免疫学方法在体内建立二氧基州介导的年龄合成的发生，然后推断出特异性二氧氧化物特异性产生的主要年龄的化学结构，开发了它们在组织中检测的方法，评估该途径在糖尿病中的年龄综合途径的重要性。预计我们的研究将提供对糖尿病年龄形成的新见解，并可能导致新的药理学剂，以防止年龄形成和糖尿病并发症。