Cyclic RGD Peptide in the Treatment of DMGS

环状RGD肽治疗DMGS

• 批准号: 6623935
• 负责人: Susanne B Nicholas
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623935
• 关键词: biological signal transduction; cell growth regulation; collagen; diabetic nephropathy; drug screening /evaluation; endocrine disorder chemotherapy; enzyme activity; extracellular matrix proteins; fibronectins; focal adhesion kinase; glomerulosclerosis; integrins; kidney cell; kidney disorder chemotherapy; kidney function; laboratory rat; laminin; metalloendopeptidases; mitogen activated protein kinase; nonhuman therapy evaluation; phosphatidylinositol 3 kinase; phosphorylation; synthetic peptide; transforming growth factors

DESCRIPTION (provided by candidate) The hallmark pathologic feature of diabetic glomerulosclerosis is mesangial expansion. In diabetic nephropathy (DN), mesangial expansion is the critical lesion that leads to the known clinical features. Increased levels of glucose, insulin, and angiotensin II (ANG ll) both cooperatively and independently stimulate the production of transforming growth factor-beta 1, which then promotes extracellular matrix (ECM) protein expansion, particularly fibronectin, laminin and collagen, by upregulating their synthesis and down-regulating their degradation. Interaction between MCs and ECM proteins occur via integrin receptors (with alpha and beta sub-units), which can be blocked by synthetic Arg-Gly-Asp (RGD) peptides and integrin antibodies. Unlike antiserum, which may cause severe side effects, cyclic RGD peptides are currently available as an effective anti-thrombotic and anti-cancer agent in humans as well as in treating ischemia-induced acute renal failure in rats. However, no-one has looked at the potential benefit of RGD peptides in treating DN. Integrin signaling is important in cellular physiology and pathophysiology. RGD peptides have also been used to define the mechanisms of integrin-mediated signaling in other cell types, but not in MC. The hypothesis of this application is that integrin-mediated attachment induces positive feedback of integrin and ECM gene expression in DN. Our preliminary studies show that RGD peptides significantly inhibited MC adhesion to fibronectin, laminin and collagen and significantly increased alpha 1, alpha 5, and beta 1 integrin sub-units in glomeruli of streptozotocin (STZ)-induced diabetic rats. Also, ANG II and insulin increased integrin expression and the IC50 of RGD peptide to inhibit MC fibronectin adhesion. The Specific Aims are 1) to quantitate the effects of cyclic RGD peptides on the progression of DMGS in STZ-induced diabetic rats; 2) to determine whether FAK, the MAPK and Pl3 kinase signaling pathways are activated by integrin-mediated MC-ECM adhesion, using RGD peptides. The successful completion of this study can provide a novel and feasible target for treatment in DN.

描述(由候选人提供) 糖尿病肾小球硬化的标志性病理特征是系膜病变 扩张。在糖尿病肾病中，系膜扩张是关键 导致已知临床特征的病变。血糖水平升高， 胰岛素和血管紧张素II(AngⅡ)既相互协作又相互独立 刺激转化生长因子-β1的产生，然后 促进细胞外基质(ECM)蛋白的扩张，尤其是 纤维连接蛋白、层粘连蛋白和胶原，通过上调它们的合成和 抑制它们的退化。巨噬细胞与细胞外基质蛋白的相互作用 通过整合素受体(带有α和β亚单位)发生，这可以是 被合成的Arg-Gly-Asp(RGD)多肽和整合素抗体阻断。不像 抗血清，可能会引起严重的副作用，环状RGD多肽 目前作为一种有效的抗血栓和抗癌药物在 此外，该药还可用于治疗大鼠的急性肾功能衰竭。 然而，还没有人关注RGD多肽在治疗中的潜在益处。 DN。整合素信号在细胞生理学和病理生理学中具有重要作用。 RGD多肽也被用来确定整合素介导的机制 在其他类型的细胞中发出信号，但在MC中不存在。这是一个假设 应用是整合素介导的依恋诱导正反馈 整合素和细胞外基质基因在糖尿病肾病中的表达。我们的初步研究表明，RGD 多肽显著抑制MC与纤维连接蛋白、层粘连蛋白和 胶原蛋白和显著增加的α1、α5和β1整合素 链脲佐菌素(STZ)诱导的糖尿病大鼠肾小球内的亚单位。还有，Ang II和胰岛素增加整合素的表达和RGD多肽对小鼠卵巢癌的IC50 抑制MC纤维连接蛋白黏附。具体目标是1)量化 环状RGD肽对链脲佐菌素诱导的糖尿病大鼠糖尿病进展的影响 2)检测FAK、MAPK和PL3激酶信号转导途径 整合素介导的MC-ECM黏附激活通路，使用RGD 多肽。这项研究的成功完成可以提供一种新颖的和 糖尿病肾病治疗的可行靶点。