REGULATING MACROPHAGE & MESANGIAL CELL BY DIABETIC ECM

糖尿病肾病是导致终末期肾病的主要原因 美国。弥漫性系膜扩张是糖尿病的重要组成部分 肾病。通过挤出开放的毛细血管袢，系膜扩张 最终导致终末期肾衰竭。该提案将尝试 显示糖尿病如何导致系膜扩张。 PI 最近 发现糖尿病与一种新的特异性的丧失有关 抑制剂（INHIB），分子量> 8,000。他认为——INHIB通常是嵌入的 在肾的系膜细胞外基质中。 INHIB 可预防 系膜基质过度扩张。在糖尿病中，INHIB 不存在或 非功能性的。这导致系膜过度扩张 - 最终导致肾功能衰竭。 所提出的实验的具体目标如下。 I) 纯化 INHIB。 II)制备抗INHIB单克隆抗体。 III) 确定原因 INHIB 在糖尿病肾系膜中没有功能。 IV) 确定 INHIB 对系膜细胞基质产生和增殖的影响。 V) 使用单克隆抗体确定器官分布 INHIB 在正常小鼠和糖尿病小鼠中的作用，并比较分子水平 这些小鼠中 INHIB 的特征。 通过了解 INHIB 的生物化学和生物学及其在体内的缺失 糖尿病肾病，针对这一主要原因的新治疗方法 最终可能会发展为肾衰竭。

Diabetic nephropathy is the leading cause of end stage renal disease in the United States. Diffuse mesangial expansion is a major component of diabetic nephropathy. By crowding out open capillary loops, this mesangial expansion eventually results in end-stage renal failure. This proposal will attempt to show how diabetes results in mesangial expansion. The PI has recently discovered that diabetes is associated with the loss of a novel specific inhibitor (INHIB), mw> 8,000. He believes-that INHIB is ordinarily embedded in the mesangial extracellular matrix of the kidney. INHIB prevents excessive mesangial matrix expansion. In diabetes, INHIB is absent or non-functional. This results in excessive mesangial expansion and-ultimately renal failure. The specific aims of the proposed experiments follow. I) To purify INHIB. II) To prepare monoclonal antibodies against INHIB. III) To determine why INHIB is nonfunctional in the diabetic renal mesangium. IV) To determine the effect of INHIB on mesangial cell matrix production and proliferation. V) To use the monoclonal antibodies to determine the organ distribution of INHIB in normal and diabetic mice, and to compare the molecular characteristics of INHIB in these mice. By understanding the biochemistry and biology of INHIB, and its absence in diabetic nephropathy, new therapeutic approaches to this major cause of renal failure may eventually be developed.