CELLULAR MECHANISM OF DIABETIC NEPHROPATHY

糖尿病肾病的细胞机制

基本信息

批准号：
6360102
负责人：
LILI FENG
金额：
$ 27.3万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2005-05-31
项目状态：
已结题

项目摘要

The objective of this proposal is the understanding of cellular mechanisms associated with the progression of diabetic nephropathy. Diabetic nephropathy is the single largest cause of end-stage renal failure in the United States. The disease is believed to be triggered by hyperglycemia in diabetes mellitus, Previous studies by others and us have show that increased expression of cytokines and growth factors play an important role in the development of kidney disease. The mitogen- activated protein kinase (MAP kinase) family members are involved in the activation of cytokines and growth factors in renal cells exposed to high glucose, but also participate in the subsequent signal transduction of these cytokines and growth factors to mediate further cellular changes. Inhibition of a MAP kinase family member, p38, by a selective inhibitor dramatically suppressed the progression of diabetic nephropathy in a rat model (streptozotocin-induced diabetes), and activation of p38 significantly accelerated the development of diabetic nephropathy. In this application, we propose to carry out studies designed to determine the function of each MAP kinase family member in diabetic nephropathy. Specifically, we will address the role of these MAP kinases in high glucose-induced gene expression and in growth factor- and cytokine- induced renal cell activation, utilizing biochemical, molecular biological, and immunological approaches. In vivo experiments will be performed to confirm the results obtained in the in vitro studies and to develop a better understanding to the role of MAP kinases in various stages of the pathogenesis of diabetic nephropathy. Insights gained in the proposed studies will lead to the development of new therapeutic strategies to this life-threatening disease.

该提案的目的是了解与糖尿病肾病进展相关的细胞机制。糖尿病肾病是美国终末期肾衰竭的最大单一原因。该疾病被认为是由糖尿病中的高血糖引发的，我们和其他人之前的研究表明，细胞因子和生长因子表达的增加在肾脏疾病的发展中发挥着重要作用。丝裂原激活蛋白激酶（MAP激酶）家族成员参与暴露于高葡萄糖的肾细胞中细胞因子和生长因子的激活，而且还参与这些细胞因子和生长因子的后续信号转导以介导进一步的细胞变化。在大鼠模型（链脲佐菌素诱导的糖尿病）中，选择性抑制剂对 MAP 激酶家族成员 p38 的抑制可显着抑制糖尿病肾病的进展，而 p38 的激活则显着加速糖尿病肾病的发展。在本申请中，我们建议开展旨在确定每个 MAP 激酶家族成员在糖尿病肾病中的功能的研究。具体来说，我们将利用生化、分子生物学和免疫学方法探讨这些 MAP 激酶在高葡萄糖诱导的基因表达以及生长因子和细胞因子诱导的肾细胞激活中的作用。将进行体内实验以证实体外研究中获得的结果，并更好地了解 MAP 激酶在糖尿病肾病发病机制各个阶段中的作用。在拟议研究中获得的见解将有助于开发针对这种危及生命的疾病的新治疗策略。