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.
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