Cyclic RGD Peptide in the Treatment of DMGS

环状RGD肽治疗DMGS

• 批准号: 6887698
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887698
• 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 扩张.在糖尿病肾病（DN）中，系膜扩张是关键的， 导致已知临床特征的病变。葡萄糖水平升高， 胰岛素和血管紧张素II（ANG II）协同或独立 刺激转化生长因子β 1的产生， 促进细胞外基质（ECM）蛋白扩增，特别是 纤连蛋白、层粘连蛋白和胶原蛋白，通过上调它们的合成， 下调它们的降解。MCs和ECM蛋白之间的相互作用 通过整合素受体（具有α和β亚单位）发生， 被合成的Arg-Gly-Asp（RGD）肽和整联蛋白抗体阻断。不像 抗血清，这可能会导致严重的副作用，环RGD肽是 目前可作为有效的抗血栓形成和抗癌剂， 人以及治疗大鼠中缺血诱导的急性肾衰竭。 然而，没有人研究过RGD肽在治疗糖尿病中的潜在益处。 DN.整合素信号传导在细胞生理学和病理生理学中是重要的。 RGD肽也已被用于定义整合素介导的细胞凋亡的机制。 在其他细胞类型中，但不在MC中。这个假设 应用是整合素介导的附着诱导正反馈 DN中整合素和ECM基因表达。我们的初步研究表明， 肽显著抑制MC与纤连蛋白、层粘连蛋白和 胶原蛋白和显著增加的α 1，α 5和β 1整合素 链脲佐菌素（STZ）诱导的糖尿病大鼠肾小球中的亚单位。此外，ANG II和胰岛素增加整合素表达和RGD肽的IC 50， 抑制MC纤连蛋白粘附。具体目标是：1）定量 环RGD肽对STZ诱导的DMGS进展的影响 糖尿病大鼠; 2）检测FAK、MAPK和P13激酶信号转导通路是否与糖尿病大鼠的糖尿病模型相一致。 整合素介导的MC-ECM粘附激活通路，使用RGD 缩氨酸这项研究的成功完成可以提供一个新的和 DN治疗的可行靶点。