LDL Modification and Diabetic Renal Dysfunction

低密度脂蛋白修饰和糖尿病肾功能障碍

• 批准号: 6988934
• 负责人: MARGO COHEN
• 金额: $ 10.43万
• 依托单位: EXOCELL, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988934
• 关键词: ACE inhibitors; combination chemotherapy; diabetes mellitus; diabetic nephropathy; dosage; drug design /synthesis /production; drug screening /evaluation; kidney function; laboratory mouse; lisinopril; low density lipoprotein; nonhuman therapy evaluation; therapy design /development

DESCRIPTION (provided by applicant): The objective of this Phase I SBIR is to determine whether preventing LDL modification, in combination with an angiotensin converting enzyme (ACE) inhibitor, is of added benefit in arresting the development and/or slowing the progression of diabetic nephropathy in a mouse model of type 2 diabetes. The rationale for this application derives from evidence linking modified LDL to diabetic glomerulosclerosis; the imperfect protection provided by inhibitors of the renin-angiotensin system (RAS), particularly in type 2 diabetes and in later stage disease; and our recent work demonstrating that a small molecule that prevents LDL modification is reno-protective in db/db mice. Notably, this compound (designated GLY-022) lessens urinary excretion of albumin and of collagen IV, a marker of renal extracellular matrix accumulation, protects against reduction in filtration function, prevents renal overproduction of TGF-beta1 protein, and restores glomerular nephrin in db/db mice. These findings suggest that GLY-022 may have a therapeutic role in the treatment of renal disease in human diabetes. Since RAS inhibitors are widely used in diabetic patients with increased albumin excretion and/or decreased glomerular filtration function, it is important to document that any proposed novel intervention strategy for diabetic renal disease confers added benefit on a background of treatment with an RAS inhibitor before lengthy and expensive clinical development of new therapies is undertaken. The specific aims of this Phase I project are to: a) Evaluate and compare the effect of lisinopril and of GLY-022, alone and in combination, on the development and progression of diabetic nephropathy in db/db mice; b) Perform dose response efficacy studies and determine optimum dosing range for meaningful effect of GLY-022, when added to chronic lisinopril therapy, on renal structure and function in diabetic rodents; and c) Assess the ability of GLY-022 added early versus later in the course of diabetes to prevent or ameliorate the structure/function changes of overt nephropathy in diabetic rodents treated with lisinopril. Positive results in this feasibility project will provide strong impetus to pursue a Phase II project and clinical development of this compound.

描述（由申请人提供）：本I阶段SBIR的目的是确定防止LDL修饰与血管紧张素转化酶（ACE）抑制剂相结合，在阻止2型糖尿病小鼠模型的糖尿病肾病的发展和/或减慢糖尿病肾病的发展方面是额外的好处。该应用程序的基本原理来自将修饰的LDL与糖尿病性肾小球硬化相关的证据。肾素 - 血管紧张素系统（RAS）抑制剂提供的不完美保护，尤其是在2型糖尿病和后期疾病中。我们最近的工作表明，一种防止LDL修饰的小分子在DB/DB小鼠中具有肾脏保护。值得注意的是，这种化合物（指定的GLY-022）降低了白蛋白和胶原蛋白IV的尿排泄，胶原蛋白IV是肾外基质基质积累的标志物，可预防降低过滤功能，可防止肾脏过量产生TGF-BETA1蛋白质，并恢复DB/DB/db/db miese glomelular niphrin in db/dbMice。这些发现表明，GLY-022在人类糖尿病的肾脏疾病治疗中可能具有治疗作用。由于RAS抑制剂被广泛用于白蛋白排泄增加和/或肾小球过滤功能增加的糖尿病患者，因此重要的是，重要的是，在长期且昂贵的临床开发新治疗的RAS抑制剂的治疗背景中，任何提议的新型糖尿病肾脏疾病的干预策略都在接受RAS抑制剂的治疗背景中增加了好处。该阶段I项目的具体目的是：a）评估和比较lisinopril和Gly-022，单独和组合对DB/DB小鼠糖尿病性肾病的发育和进展的影响； b）进行剂量反应疗效研究，并确定GLY-022有意义效应的最佳剂量范围，当添加到慢性赖诺普利疗法中时，对糖尿病啮齿动物的肾脏结构和功能； c）评估GLY-022早期与糖尿病过程中早期增加的能力，以预防或改善用lisinopril治疗的糖尿病啮齿动物中明显的肾病的结构/功能变化。这个可行性项目的积极结果将为追求该化合物的II期项目和临床开发提供强大的动力。