NO-donor/SOD-mimetics for diabetic nephropathy

NO-供体/SOD-模拟物治疗糖尿病肾病

• 批准号: 6832967
• 负责人: ELWOOD E. REYNOLDS
• 金额: $ 13.4万
• 依托单位: MANDALMED, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832967
• 关键词: analog; antioxidants; biomimetics; chemoprevention; diabetes mellitus; diabetes mellitus therapy; diabetic nephropathy; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; free radical oxygen; free radical scavengers; hyperglycemia; kidney cell; kidney disorder chemotherapy; kidney function; kidney pharmacology; laboratory rat; nitric oxide; oxidative stress; short chain fatty acid; superoxide dismutase; tissue /cell culture; vascular endothelium; vasomotion

DESCRIPTION (provided by applicant): Vascular disease is the principal cause of morbidity and mortality in patients with diabetes, leading to nephropathy, retinopathy, neuropathy, and ischemic disease. Hyperglycemic damage to vascular endothelial cells is a major cause of these vascular complications of diabetes. This endothelial dysfunction is caused by oxidative stress induced by hyperglycemia, resulting in both the increased production of reactive oxygen species (ROS) and decreased bioavailability of nitric oxide (NO). Hyperglycemia also causes similar oxidative stress in renal mesangial cells, which leads to mesangial matrix expansion, glomerosclerosis, and renal functional impairment. We have developed a novel drug for treatment of hyperglycemia induced endothelial and mesangial cell dysfunction. OX029 is a bifunctional NO-donor/SOD-mimetic which is a derivative of lipoic acid, The major goals of this proposal are to (1) determine the efficacy of OX029 to prevent endothelial dysfunction and renal injury in the diabetic streptozotocin-treated rat, and (2) design and synthesize 20 novel analogs of OX029 and test their efficacy in isolated blood vessels and cultured renal mesangial cells exposed to hyperglycemia. If OX029 is efficacious in preventing renal injury in STZ-diabetic rats, we plan to submit a Phase II grant to: (1) test one or two OX029 analogs for prevention of diabetic nephropathy in vivo, (2) expand the in vivo studies in STZ-diabetic rats to a long term study (6-9 months) to include other endpoints of renal pathology, such as histology and morphometry, glucose tolerance and insulin sensitivity, and renal function, and (3) expand the in vivo studies to include another animal model of diabetes, the db/db mouse which spontaneously develops type II diabetes. The long-term commercial goal is to develop an orally active drug which can be given to both type I and type II diabetics to attenuate the renal damage caused by chronic hyperglycemia, and also attenuate other vascular complications of diabetes.

描述（由申请人提供）：血管疾病是糖尿病患者发病率和死亡率的主要原因，导致肾病，视网膜病变，神经病和缺血性疾病。对血管内皮细胞的高血糖损害是糖尿病血管并发症的主要原因。这种内皮功能障碍是由高血糖诱导的氧化应激引起的，导致活性氧（ROS）的产生增加和一氧化氮生物利用度降低（NO）。高血糖还会引起肾小管膜细胞中相似的氧化应激，从而导致肾小球基质扩张，肾小球层状和肾功能障碍。我们已经开发了一种用于治疗高血糖诱导内皮和肾小球功能障碍的新药。 OX029是一种双功能的无偏/模拟模拟物，是脂酸的导数，该提案的主要目标是（1）确定OX029在防止内皮功能障碍和肾脏内皮功能障碍和肾脏链抗链球菌链球菌毒素造成的效果的效果上的效果，并鉴于20个新颖的型号的象征和同步的象征。血管和培养的肾小管细胞暴露于高血糖。如果OX029有效预防STZ糖尿病大鼠肾脏损伤，我们计划将II阶段赠款提交给：（1）测试一个或两种OX029预防体内糖尿病性肾病的类似物，（2）将STZ-糖尿病研究的体内研究扩展到长期的病理学（6--9--9--9--9--9--9--9--9--9--9--9-9-9-9-9-9-9-9-9-9-9-9-9-9）葡萄糖耐受性和胰岛素敏感性和肾功能，以及（3）扩展体内研究，包括另一种糖尿病动物模型，即自发发展II型糖尿病的DB/DB小鼠。长期的商业目标是开发一种可以给予I型和II型糖尿病患者的口服活性药物，以减轻慢性高血糖造成的肾脏损害，并减轻糖尿病的其他血管并发症。