Up to 60% of SLE patients develop clinical evidence of kidney injury, termed lupus nephritis (LN). LN is thought to be caused by glomerular immune complex deposition activating an inflammatory cascade that injures glomerular cells, leading to proteinuria and loss of filtration capacity. LN is classified based on renal histopathology into si classes, of which proliferative LN (ISN/RPS class III or IV) is most likely to cause renal failure. Most studies examining the causes of proliferative LN have focused on the nephritogenic potential of anti-nuclear antibodies, diverting attention from a potential role for tissue/cell-specific autoantibodies. There is increasing evidence that autoantibodies to tissue specific target antigens contribute to the pathogenesis of many glomerular diseases, including LN. Our preliminary data show that sera from patients with proliferative LN contain autoantibodies to human glomerular proteins, including annexin A2 and moesin. These findings support our central hypothesis that autoantibodies targeting glomerular proteins, including annexin A2 and moesin, result in immune complex deposition that causes proliferative LN. This mentored career development proposal will focus on further characterization of autoantibodies to annexin A2 and moesin in proliferative LN, validation of those autoantibodies as biomarkers for disease, examination of the functional changes in podocytes and mesangial cells exposed to those autoantibodies, and evaluation of the nephritogenic potential of those antibodies in animal models. As evidenced by the advances in understanding primary membranous nephropathy after the identification of target antigens, this will lead to improved understanding of the pathogenic mechanisms of disease, and provide new diagnostic and prognostic biomarkers. This mentored career development award also will provide protected time for the applicant to develop the skills required to become an independent physician-scientist, investigating clinical and basic aspects of lupus nephritis, through an individualized career development plan which has been developed by the mentorship team.
The objective of this mentored Career Development proposal is to characterize cell/tissue specific nephritogenic autoantibodies that cause proliferative LN (class III/IV). This research is expected to establish the pathophysiologic basis for proliferative LN as well as identify biomarkers for the diagnosis of this disease, providing the technologic and intellectual framework necessary for the applicant to develop an independent research program in this discipline.
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