CELLULAR MECHANISM OF DIABETIC NEPHROPATHY

糖尿病肾病的细胞机制

• 批准号: 6740223
• 负责人: LILI FENG
• 金额: $ 23.02万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740223
• 关键词: Adenoviridae; JUN kinase; RNase protection assay; cell proliferation; cytokine; diabetic nephropathy; enzyme activity; epidermal growth factor; extracellular matrix; gene induction /repression; glucose; in situ hybridization; kidney cell; laboratory rabbit; laboratory rat; luciferin monooxygenase; mitogen activated protein kinase; recombinant virus; renal toxin; streptozotocin; transforming growth factors

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.

该建议的目的是了解与糖尿病肾病进展相关的细胞机制。糖尿病性肾病是美国末期肾衰竭的最大原因。人们认为该疾病是由糖尿病中高血糖引发的，其他人和美国的先前研究表明，细胞因子和生长因子的表达增加在肾脏疾病的发展中起着重要作用。有丝分裂原活化的蛋白激酶（MAP激酶）家族成员参与暴露于高葡萄糖的肾细胞中的细胞因子和生长因子的激活，但也参与了这些细胞因子和生长因子的随后信号转导，以介导进一步的细胞变化。通过选择性抑制剂对MAP激酶家族成员P38的抑制作用急剧抑制了大鼠模型中糖尿病性肾病的进展（链蛋白酶诱导的糖尿病），p38的激活显着加速了糖尿病肾病的发展。在此应用中，我们建议进行旨在确定糖尿病肾病中每个MAP激酶家族成员功能的研究。具体而言，我们将利用生化，分子生物学和免疫学方法来解决这些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活化中的作用。将进行体内实验，以确认体外研究中获得的结果，并更好地了解MAP激酶在糖尿病性肾病发病机理的各个阶段的作用。在拟议的研究中获得的见解将导致这种威胁生命的疾病的新治疗策略。