Clusterin and Renal Injury

簇蛋白和肾损伤

• 批准号: 6395252
• 负责人: MARK E. ROSENBERG
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6395252
• 关键词: Arthus phenomenon; antibody receptor; biological transport; clusterin; gene targeting; genetic models; genetically modified animals; glomerulonephritis; immune complex; kidney cell; kidney disorder; laboratory mouse; mesangium; pathologic process; protein sequence; receptor expression

Clusterin is a circulating glycoprotein which is also widely distributed throughout the body and further induced following injury and disease. Deficiency of clusterin impairs immune complex clearance and leads to a progressive glomerulopathy characterized by immune complex deposition in the mesangium. The objective of this grant is to use the model of clusterin deficiency to study the physiologic and pathophysiologic function of clusterin focusing on its role in the pathogenesis of immune complex mediated disease. In SPECIFIC AIM 1, the the role of clusterin in the clearance of immune complexes will be studied by comparing the in vivo clearance of injected immune complexes in clusterin deficient and wild-type mice. The ability of clusterin to facilitate the uptake and degradation of immune complexes by Kupffer and endothelial cells, components of the liver reticuloendothelial system, will then be tested. Finally the amino acid sequences of clusterin responsible for its interaction with immune complexes will be identified using a panel of peptides derived from the clusterin sequence. In SPECIFIC AIM 2, we will test whether clusterin modulate the interaction of immune complexes with Fc receptors present on mesangial or mononuclear cells. We will first examine the Fc receptor expression in mesangial cells from clusterin deficient and wildtype mice. We will then examine the effect of clusterin on immune complex binding and activation of cultured mesangial cells isolated from clusterin deficient and wild type mice. The effect of clusterin on the immune complex mediated inflammatory response seen in the Arthus reaction will be studied to determine if clusterin deficiency modulates an in vivo Fc receptor dependent immune reaction. In SPECIFIC AIM 3, the ability of clusterin to modify immune complex mediated disease will be tested in two induced models of glomerulonephritis (GN), one to in situ formed immune complexes (nephrotoxic serum nephritis) and the other to circulating immune complexes (apoferritin GN). We will then study a genetic model (SLE) of immune complex mediated GN in clusterin deficient and wild type mice. In summary, capitalizing on the striking glomerular pathology of the clusterin knock-out mice, we expect to provide new and fundamental understanding Capitalizing on the striking glomerular pathology of the clusterin knockout mice, we expect to provide new and fundamental understanding of the glomerular accumulation and inflammatory processing of immune complexes. These finding should have wide importance not only to the mechanism of and susceptibility to "immune complex" renal disease, but also for basic pathways of systemic clearance of toxic and/or denatured proteins.

簇蛋白是一种循环的糖蛋白，也广泛分布在整个体内，并在受伤和疾病后进一步诱导。簇蛋白的缺乏会损害免疫复合物的清除率，并导致肾小球病变，其特征是中膜中的免疫复合物沉积。 该赠款的目的是利用簇素缺乏症模型来研究簇蛋白的生理和病理生理功能，重点是其在免疫复杂介导的疾病的发病机理中的作用。在特定的目标1中，将研究簇蛋白在免疫复合物清除率中的作用，以比较簇蛋白缺乏和野生型小鼠中注射的免疫复合物的体内清除率。 然后，将测试簇素的能力促进肝网状内皮系统的成分Kupffer和内皮细胞对免疫复合物摄取和降解的能力。最后，将使用源自簇蛋白序列的一组肽面板来鉴定簇素与免疫复合物相互作用的氨基酸序列。在特定的目标2中，我们将测试簇蛋白是否调节免疫复合物与肾小球或单核细胞上存在的FC受体的相互作用。我们将首先检查来自簇蛋白缺乏和野生型小鼠的细胞内膜细胞中的FC受体表达。 然后，我们将检查簇蛋白对从缺乏簇和野生型小鼠分离的培养的介膜细胞的免疫复合物结合和激活的影响。 将研究簇素对Arthus反应中免疫复合物介导的炎症反应的影响，以确定簇蛋白缺乏是否调节体内FC受体依赖性免疫反应。在特定目标3中，将在两个诱导的肾小球肾炎模型（GN）模型中测试簇蛋白修饰免疫复合介导的疾病的能力，一种是原位形成的免疫复合物（肾毒性血清肾炎），另一种是循环的免疫复合物（Apoferritin GN）。 然后，我们将研究簇蛋白缺乏和野生型小鼠中免疫复合物介导的GN的遗传模型（SLE）。总而言之，利用簇蛋白敲除小鼠的惊人肾小球病理学，我们希望能够利用簇敲除小鼠的惊人的肾小球病理学来提供新的理解，我们希望对肾小球积累和免疫复合物的炎症处理提供新的和基本的了解。 这些发现不仅对“免疫复杂”肾脏疾病的机制和易感性具有广泛的重要性，而且还应该对有毒和/或变性蛋白的全身清除率的基本途径。