RENAL RESPONSE TO INJURY

肾脏对损伤的反应

• 批准号: 2518370
• 负责人: WILLIAM G COUSER
• 金额: $ 71.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518370
• 关键词: injury; kidney disorder; pathologic process

This proposal is a multidisciplinary research effort which is directed at better understanding the renal response to several forms of glomerular injury that lead to chronic renal failure. The Center will support research on two molecules which have not been previously associated with renal disease (SPARC is an important regulator of glomerular cell proliferation and attachment and that increased osteopontin (OPN) in tubules mediates interstitial macrophage infiltration leading to fibrosis and progressive renal disease. In Project 1, Drs. Bassuk and Sage will explore the structural basis for properties of the SPARC molecule that may modulate tahe mesangial response to injury including effects on mesangial cell morphology, attachment to matrix, proliferation and growth. In Project 2, Drs. Couser and Sage will assess the role of increased SPARC expression in glomerular mesangial and epithelial cells in vivo as this relates to modulation of cell proliferation and alterations in cell matrix interaction. In Project 3, Dr. Giachelli will conduct basic studies of the factors which regulate OPN chemotaxis and adhesive functions and of the mechanisms which regulate OPN gene expression in several cell types at a molecular level. In Project 4, Drs. Giachelli and Johnson will test the hypothesis that OPN is an important mediator of progressive renal disease by performing sequential studies of the site and extent of OPN protein and MRNA expression as it relates to various other cellular and structural findings in the mesangioproliferative, aminonucleoside and cyclosporin-induced models of progressive renal disease, determine if OPN expression is mediated by AII and assess the consequences of blocking OPN activity in vivo with neutralizing antibodies or specific blocking peptides. In Project 5, Dr. Schwartz will study the mitogenic factors involved in stimulation of microvascular smooth muscle proliferation in hypertensive injury, examine the expression of genes characteristic of injured neointima in large vessels as they relate to histopathologic changes in kidney microvessels in response to hypertensive injury and examine the factors which regulate recovery of an injured renal microvessel from hypertensive injury. In the Morphology and Clinical Application Core, Dr. Alpers will extend the observations made in projects 1-5 to studies of normal and diseased human kidney tissue. This Center will be administered through an Administrative Core directed by Dr. Couser.

这项建议是一项多学科的研究工作， 在更好地理解肾脏对几种形式的肾小球疾病的反应方面， 导致慢性肾衰竭损伤。 中心将支持 对两种以前没有与之相关的分子的研究 肾脏疾病（肾小球疾病）是肾小球细胞的重要调节因子， 增殖和附着以及骨桥蛋白（OPN）的增加 肾小管介导间质巨噬细胞浸润，导致纤维化 和进行性肾病。 在项目1中，Bassuk博士和Sage博士将探讨 可调节系膜细胞的β-淀粉样蛋白分子的性质 对损伤的反应包括对系膜细胞形态的影响， 附着于基质、增殖和生长。 在项目2中，博士。 Cherer和Sage将评估增加β-淀粉样蛋白表达的作用， 肾小球系膜和上皮细胞在体内，因为这涉及到 调节细胞增殖和细胞基质的改变 互动 在项目3中，Giachelli博士将进行以下基础研究： 调节骨桥蛋白趋化性和粘附功能的因子， 在几种细胞类型中调节OPN基因表达的机制 在分子水平上。 在项目4中，吉亚切利博士和约翰逊博士将测试 假设OPN是进行性肾损害的重要介质， 通过对骨桥蛋白的部位和程度进行连续研究， 蛋白质和mRNA的表达，因为它涉及到各种其他细胞和 系膜增生、羊膜侧和 环孢素诱导的进行性肾病模型，确定是否 OPN表达由AII介导，并评估阻断的后果 中和抗体或特异性阻断的体内OPN活性 缩氨酸 在项目5中，施瓦茨博士将研究促有丝分裂因子 参与刺激微血管平滑肌增殖， 高血压损伤，检查基因的表达特征， 大血管中损伤的新生内膜与组织病理学相关 高血压损伤时肾脏微血管的变化， 检查调节受损肾脏恢复的因素 高血压损伤的微血管。 在形态学和临床 应用核心，阿尔珀斯博士将扩展在 项目1-5涉及正常和患病的人肾组织的研究。 这 中心将通过行政核心进行管理， 博士更好。