Pathogenic Mechanisms Underlying Diabetic Retinopathy

糖尿病视网膜病变的发病机制

• 批准号: 6904443
• 负责人: MELVIN EDWARD MEDOF
• 金额: $ 34.43万
• 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: 2004-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6904443
• 关键词: CD antigens; active sites; clinical research; complement; diabetes mellitus; diabetic retinopathy; disease /disorder etiology; disease /disorder model; genetically modified animals; glucose; human subject; hyperglycemia; inflammation; laboratory mouse; mass spectrometry; matrix assisted laser desorption ionization; membrane proteins; protein structure function; retina; ribose; streptozotocin; tissue /cell culture

DESCRIPTION (provided by applicant): The pathogenic processes that give rise to microangiopathic retinopathy and other vascular complications in diabetes are poorly understood. Several new lines of evidence have pointed toward inflammation as playing a heretofore unrecognized role. Retinal cells and vasculature and other self cells are protected from attack by autologous complement proteins by a set of intrinsic membrane regulatory proteins. These regulators are the decay accelerating factor (DAF or CD55), the membrane cofactor protein (MCP or CD46), and the membrane inhibitor of reactive lysis (CD59). Previous studies from our lab have shown that all three surface proteins are highly expressed in the retina and its associated vasculature in levels similar to those on glomerular cells and on systemic vasculature, sites where intrinsic regulatory activity is critical. In recent in vitro work, we have shown that DAF's regulatory function is 1) >90% inactivated by incubation with glucose or ribose, 2) rapidly abrogated by methylglyoxal incubation, and 3) lost due to modification of one or more active site lysine and arginine residues, the latter to argprymidine. In in vivo work, we have shown that endogenous DAF protein isolated from diabetic retinas is modified by several sugar adducts including argpyrimidine. The proposed studies are directed toward 1) determining the functional effects of chemical modifications in DAF, MCP, (and CD59) that are induced by hyperglycemia and other metabolic abnormalities that pertain in the diabetic state, 2) structurally characterizing the types and sites of the modifications on the regulators, 3) analyzing the functions and structures of endogenous DAF, MCP, (and CD59) proteins isolated from retinas and other tissues of diabetics, and 4) examining whether the pathological changes that are associated with retinopathy and other diabetic complications develop more rapidly in Daf1-/- (murine DAF homolog), Crry-/- (murine MCP surrogate), CD59a-/- (murine CD59 homolog) and double Daf1-/- / -/- Curry-/- or Daf1-/- / CD59a-/- mice experimentally made diabetic with streptozotocln. Since vasculopathy and retinopathy are debilitating complications that eventually affect most patients with diabetes, fully understanding the mechanisms involved in their development is important in designing effective therapeutic interventions.

描述（由申请人提供）：引起微型病变性视网膜病和糖尿病中其他血管并发症的致病过程知之甚少。几条新的证据表明，炎症是迄今无法识别的角色。视网膜细胞和脉管系统和其他自我细胞受到一组固有的膜调节蛋白的自体补体蛋白的攻击。这些调节剂是衰减加速因子（DAF或CD55），膜辅因子蛋白（MCP或CD46）和反应性裂解的膜抑制剂（CD59）。我们实验室的先前研究表明，所有三种表面蛋白在视网膜及其相关的脉管系统中都高度表达，其水平与肾小球细胞和全身性脉管系统相似，即固有调节活性至关重要的地点。在最近的体外工作中，我们表明DAF的调节功能为1）> 90％通过与葡萄糖或核糖孵育，2）因甲基糖孵育而迅速废除，而3）由于一种或多种活性位点赖氨酸和精氨酸残基的修饰而丢失，而后者是ArgPrymidine。在体内工作中，我们已经表明，从糖尿病视网膜中分离出的内源性DAF蛋白是通过包括Argpyrimidine在内的几种糖加合物来改变的。 The proposed studies are directed toward 1) determining the functional effects of chemical modifications in DAF, MCP, (and CD59) that are induced by hyperglycemia and other metabolic abnormalities that pertain in the diabetic state, 2) structurally characterizing the types and sites of the modifications on the regulators, 3) analyzing the functions and structures of endogenous DAF, MCP, (and CD59) proteins isolated from retinas and other tissues of diabetics, and 4) examining whether the pathological changes that are associated with retinopathy and other diabetic complications develop more rapidly in Daf1-/- (murine DAF homolog), Crry-/- (murine MCP surrogate), CD59a-/- (murine CD59 homolog) and double Daf1-/- / -/- Curry-/- or DAF1 - / - /CD59A - / - 用链链球菌实验进行的糖尿病。由于血管病和视网膜病是令人衰弱的并发症，最终影响大多数糖尿病患者，因此充分了解其发育中涉及的机制对于设计有效的治疗干预措施很重要。