RENAL RESPONSE TO INJURY

这项建议是一项多学科的研究工作，旨在 更好地了解肾脏对几种形式的肾小球的反应 导致慢性肾功能衰竭的损伤。该中心将支持 关于两个以前未与之相关的分子的研究 肾脏疾病(SPARC是肾小球细胞的重要调节因子 骨桥蛋白(OPN)在骨桥蛋白中的表达 肾小管介导间质巨噬细胞浸润导致纤维化 和进行性肾脏疾病。 在项目1中，Bassuk博士和Sage博士将探索 可调节Tahe系膜的SPARC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，Dr。 Couser和Sage将评估SPARC表达增加在 肾小球系膜细胞和肾小球上皮细胞与肾小球系膜细胞 细胞增殖的调控和细胞基质的改变 互动。在项目3中，贾切利博士将对 调节骨桥蛋白趋化和黏附功能的因素 骨桥蛋白基因在几种细胞类型中表达的调控机制 在分子水平上。在项目4中，贾切利博士和约翰逊博士将测试 骨桥蛋白是进展性肾脏重要介质的假说 通过对OPN的位置和范围进行顺序研究来治疗疾病 蛋白质和mRNA的表达，因为它与其他各种细胞和 系膜增生性、氨基核苷类和 环孢素诱导的进展性肾病模型，确定 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对OPN体内活性的影响 多肽。在项目5中，施瓦茨博士将研究有丝分裂因子 参与刺激血管内皮细胞微血管的增殖 高血压损伤后，检测其特有基因的表达 大血管损伤新生内膜与组织病理学的关系 高血压损伤后肾脏微血管的变化及意义 探讨影响受损肾脏恢复的因素 高血压损伤的微血管。在形态和临床上 应用程序核心，Alpers博士将扩展在 项目1-5对正常和疾病的人类肾组织进行研究。这 中心将通过由领导的管理核心进行管理 考瑟医生。

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.