POLY(ADP) RIBOSE SYNTHETASE AND AUTOIMMUNE DIABETES

聚（ADP）核糖合成酶与自身免疫性糖尿病

• 批准号: 6178235
• 负责人: JON G MABLEY
• 金额: $ 11.13万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178235
• 关键词: adenine phosphoribosyltransferase; apoptosis; cellular pathology; disease /disorder model; drug design /synthesis /production; enzyme inhibitors; hyperglycemia; insulin dependent diabetes mellitus; laboratory mouse; necrosis; pancreatic islets; peroxynitrites; pyrones

DESCRIPTION (adapted from the applicant's abstract): The cellular and molecular mechanisms of free radical-related pancreatic islet destruction are incompletely understood. Pharmacological modulation of this islet cell death may provide novel avenues for the experimental therapy of diabetes. Recent studies in isolated islet cells, and other cell types demonstrate that peroxynitrite and hydrogen peroxide, potent oxidants produced during immune-cell mediated islet cell attack, trigger an intracellular cascade culminating in cellular energy failure. DNA strand-breakage triggered by hydrogen peroxide and peroxynitrite is recognized by a specific domain of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). This results in the activation of PARS which initiates an energy consuming inefficient repair cycle, with resultant depletion of dinucleotide pools, slowing the rate of glycolysis and mitochondrial respiration, reducing ATP synthesis. Thus, PARS acts as a terminal mediator of cellular energetic collapse leading to cellular necrosis. The preliminary data show that pharmacological inhibition of PARS with 5-iodo-6-amino-1,2 benzopyrone (INH2BP), a novel, potent inhibitor of PARS reduces the development of hyperglycemia and islet cell destruction in a rot model of streptozotocin-induced diabetes. Furthermore, data from the group, and also from two other groups of investigators demonstrate that PARS deficient (knockout) mice are resistant against streptozotocin-induced diabetes. Because the streptozotocin-model is not fully predictable of the human situation, the first aim of the current protocol is aimed at investigating the role of PARS activation in the pathophysiology of spontaneous autoimmune diabetes: PARS deficient mice will be back-crossed with the NOD mice, and the development of diabetes will be investigated in this model. The course of pancreatic insulin depletion, the course of insulitis, and the development of hyperglycemia will be monitored. They will also test the effect of the PARS inhibitor INH2BP on the course of diabetes development in the NOD model. The second aim of the proposed studies is to perform in vitro studies in islets from wild type and PARS deficient mice in order to define the mode of cell death (necrosis and apoptosis) induced by peroxynitrite, and to define the role of PARS in the process. The current proposal will provide (1) novel mechanistic information on the mechanism of autoimmune diabetes, and (2) will result in data which will help the company in making a strategic decision for the preclinical development of a novel, potent, orally active PARS inhibitor.

描述（改编自申请人的摘要）： 自由基相关的胰岛破坏机制是 不完全理解。这种胰岛细胞死亡的药理学调节 可能为糖尿病的实验性治疗提供新的途径。最近 对分离的胰岛细胞和其它细胞类型的研究表明， 过氧亚硝酸盐和过氧化氢，在生产过程中产生的强氧化剂， 免疫细胞介导胰岛细胞攻击，触发细胞内级联反应 最终导致细胞能量衰竭DNA链断裂由 过氧化氢和过氧亚硝酸根的识别是由一个特定的域的 核酶聚（ADP-核糖）合成酶（PARS）。这导致 激活PARS，启动能量消耗低效修复 循环，导致二核苷酸池耗尽，减慢合成速率 糖酵解和线粒体呼吸，减少ATP合成。因此，PARS 作为细胞能量崩溃的终端介质，导致细胞 坏死初步数据表明，PARS的药理学抑制作用 与5-碘-6-氨基-1，2-苯并吡喃酮（INH 2BP），一种新的，有效的PARS抑制剂， 减少腐烂中高血糖和胰岛细胞破坏的发展 链脲佐菌素诱导的糖尿病模型。此外，该集团的数据，以及 另外两组研究人员也证明，PARS缺乏 （基因敲除）小鼠对链脲霉素诱导的糖尿病具有抗性。因为 链脲佐菌素模型不能完全预测人类的情况， 当前协议的第一个目的是研究PARS的作用 自发性自身免疫性糖尿病的病理生理学激活 缺陷小鼠将与NOD小鼠回交，并且 将在该模型中研究糖尿病。胰胰岛素的疗程 消耗，胰岛炎的过程和高血糖的发展将 被监控。他们还将测试PARS抑制剂INH 2BP对 NOD模型中糖尿病的发展过程。第二个目标 建议的研究是在来自野生型的胰岛中进行体外研究， PARS缺陷小鼠，以确定细胞死亡的模式（坏死和坏死）。 凋亡），并确定PARS在过亚硝酸盐诱导的细胞凋亡中的作用。 过程目前的建议将提供（1）新的机制信息， 自身免疫性糖尿病的机制，和（2）将导致数据， 帮助公司做出临床前开发的战略决策 一种新型的、有效的、口服活性PARS抑制剂。