MOLECULAR MEDIATORS OF DIABETIC RENAL HYPERTROPHY

描述：(改编自申请者的摘要)--糖尿病神经病变 30%-40%的患者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。因此， 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。糖尿病所特有的肾病 糖尿病以肾小球性高血压和系膜细胞肥大为特征 和增生，以及肾小球基底部广泛的重塑 薄膜。这些现象可能是由于……的行为造成的 血管收缩活性多肽，特别是内皮素(ET-1)和 血管紧张素II(A-II)。此外，高血糖本身以及 肾小球高血压的生理应激可能参与肾小球 肥大和基底膜重塑。很明显， 细胞信号转导通路在偶联反应中起着重要作用 血管活性多肽对糖尿病神经病变的生物学后果。 的确，高血糖、ET-1和A-II以及机械性/高血压 应激可诱导c-fos和c-jun。因此，完全理解 血管活性多肽招募的细胞信号转导机制， 高血压应激和再灌流损伤对高血压的发展至关重要。 更有效的治疗糖尿病神经病变的方法。 调查人员已经确定了两个信号网络，它们强烈地 由ET-1和高血压应激(细胞伸展)激活。这些路径 已被证明在Fos和Jun诱导过程中对多种 通过招募细胞外两个亚家族的应激刺激 信号调节蛋白激酶(ERKs)，即应激激活的蛋白激酶 (SAPKs，又称JNK)和p38。这是下一阶段的目标 确定SAPKs和P38S如何受到分歧者监管的项目 ET-1应激、细胞伸展和再灌注损伤，以及SAPKs如何 P38参与了糖尿病神经病变的发病机制。首先， 研究人员将使用常规生化分析的组合来 鉴定丝裂原活化蛋白激酶(MAPK)/ERK激酶的成员 (MEK)家族，存在于系膜细胞中，激活SAPKs和p38和 它们本身受ET-1、A-II或细胞伸展的调节。下一首, 他们将确定A-II、ET-1和细胞伸展的机制 在系膜细胞中，募集G蛋白激活SAPKs和P38S。在……里面 特别是，他们将专注于三聚体和RAS超家族G蛋白，如 以及MEK-Kinase-1(MEKK1)，一种丝氨酸/Thr激酶，也被认为调节 SAPK途径。最后，他们将使用腺病毒表达构建物来 干扰肾小球系膜细胞SAPK和p38的激活及其作用 这些扰动中的两个已知发生在 糖尿病肾病中的系膜细胞：细胞肥大和 过量的基质沉积。他们希望，这些研究将扩大我们的 对糖尿病肾脏中信号转导的认识和贡献 利用信号转导技术治疗糖尿病肾病的研究进展 组件作为目标。

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.