MOLECULAR MEDIATORS OF DIABETIC RENAL HYPERTROPHY

糖尿病肾肥大的分子介质

基本信息

批准号：
6684375
负责人：
John M Kyriakis
金额：
$ 5.59万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-10-01 至 2003-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6684375
关键词：
angiotensin II animal tissue biological signal transduction diabetic nephropathy disease /disorder model endothelin enzyme activity hormone regulation /control mechanism injury /disease stressor insulin dependent diabetes mellitus mitogen activated protein kinase molecular pathology phosphorylation protein kinase tissue /cell culture

项目摘要

DESCRIPTION: (Adapted from the applicant's abstract) - Diabetic neuropathy progressing to chronic renal failure develops in 30-40% of individuals with type I diabetes and 5-10% of individuals with type II diabetes. As such, diabetic neuropathy is perhaps the major determinant of premature mortality in the type I diabetic. The renal disease characteristic of diabetes mellitus is marked by glomerular hypertension and mesangial cell hypertrophy and hyperplasia, as well as extensive remodeling of the glomerular basement membrane. These phenomena may arise as a result of the actions of vasoconstrictive vasoactive peptides, especially endothelin (ET-1) and angiotensin-II (A-II). In addition, hyperglycemia itself, along with the physical stress of glomerular hypertension may contribute to glomerular hypertrophy and basement membrane remodelling. It has become clear that cellular signal transduction pathways play an important role in coupling vasoactive peptides to the biological consequences of diabetic neuropathy. Indeed, hyperglycemia, ET-1, and A-II, as well as mechanical/hypertensive stress can induce c-fos and c-jun. Thus a complete understanding of the cellular signal transduction mechanisms recruited by vasoactive peptides, hypertensive stress, and reperfusion inhjury is crucial to the development of more effective treatments for diabetic neuropathy. The investigators have identified two signaling networks which are strongly activated by ET-1 and hypertensive stress (cell stretching). These pathways have been shown to mediate fos and jun induction in response to a variety of stresssful stimuli by recruiting two subfamilies of the extracellular signal-regulated kinases (ERKs), the stress-activated protein kinases (SAPKs, also called JNKs) and p38. It is the goal of the next phase of this project to determine how the SAPKs and p38s are regulated by the divergent stresses of ET-1, cell stretching, and reperfusion injury, and how the SAPKs and p38 contribute to the pathogenesis of diabetic neuropathy. First, the investigator will use a combination of conventional biochemical assays to identify members of the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) family, presen in mesangial cells which activate the SAPKs and p38 and which are themselves regulated by ET-1, A-II, or cell stretching. Next, they will determine the mechanisms by which A-II, ET-1, and cell stretching in mesangial cells recruit G proteins to activate the SAPKs and p38s. In particular they will focus on trimeric and Ras superfamily G proteins, as well as MEK-kinase-1 (MEKK1), a Ser/thr kinase also thought to regulate the SAPK pathway. Finally, they will use adenoviral expression constructs to perturb SAPK and p38 activation in mesangial cells and examine the effects of these perturbations on two biological responses known to occur in mesangial cells during diabetic nephropathy: cellular hypertrophy and excess matrix deposition. These studies, they hope, will expand our knowledge of signal transduction in the diabetic kidney and contribute to the development of novel treatments for diabetic nephropathy using signaling components as targets.

描述：（改编自申请人的摘要）- 糖尿病神经病 30-40% 的患者会进展为慢性肾功能衰竭 I 型糖尿病和 5-10% 的 II 型糖尿病患者。像这样，糖尿病神经病变可能是过早死亡的主要决定因素在 I 型糖尿病中。糖尿病肾病的特点糖尿病的特点是肾小球高血压和系膜细胞肥大和增生，以及肾小球基底的广泛重塑膜。这些现象可能是由于以下人员的行为而引起的：血管收缩血管活性肽，尤其是内皮素 (ET-1) 和血管紧张素-II (A-II)。此外，高血糖本身以及肾小球高血压的身体压力可能会导致肾小球高血压肥大和基底膜重塑。已经清楚的是细胞信号转导途径在耦合中发挥着重要作用血管活性肽对糖尿病神经病变的生物学后果。事实上，高血糖、ET-1 和 A-II，以及机械性/高血压应激可诱发c-fos和c-jun。从而全面了解血管活性肽募集的细胞信号转导机制，高血压应激和再灌注损伤对于发育至关重要糖尿病神经病变的更有效治疗方法。研究人员发现了两个信号网络由 ET-1 和高血压应激（细胞拉伸）激活。这些途径已被证明可以介导 fos 和 jun 诱导以响应各种通过招募细胞外细胞的两个亚科来进行应激刺激信号调节激酶 (ERK)，应激激活蛋白激酶（SAPK，也称为 JNK）和 p38。这是下一阶段的目标确定 SAPK 和 p38 如何受不同监管机构监管的项目 ET-1 的应激、细胞拉伸和再灌注损伤，以及 SAPK 的作用 p38 和 p38 有助于糖尿病神经病变的发病机制。首先，研究人员将结合使用常规生化检测来鉴定丝裂原激活蛋白激酶 (MAPK)/ERK 激酶的成员 (MEK) 家族，存在于激活 SAPK 和 p38 的系膜细胞中它们本身受 ET-1、A-II 或细胞拉伸调节。下一个，他们将确定 A-II、ET-1 和细胞拉伸的机制系膜细胞中招募 G 蛋白来激活 SAPK 和 p38。在特别是他们将重点关注三聚体和 Ras 超家族 G 蛋白，因为以及 MEK-kinase-1 (MEKK1)，一种 Ser/thr 激酶也被认为可以调节 SAPK途径。最后，他们将使用腺病毒表达构建体干扰系膜细胞中 SAPK 和 p38 的激活并检查其影响这些扰动对已知发生在的两种生物反应糖尿病肾病期间的系膜细胞：细胞肥大和过量的基质沉积。他们希望这些研究能够扩大我们的研究范围了解糖尿病肾脏中的信号转导并有助于利用信号传导开发糖尿病肾病的新疗法组件作为目标。