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Principal Investigator: Dawn Caster
Organization: UNIVERSITY OF LOUISVILLE
Fiscal Year: 2019
Award: $165,780
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
DESCRIPTION (provided by applicant): 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.
Terms: <7S Gamma Globulin><Actins><Address><Affect><American><Animal Model><Animal Models and Related Studies><Annexins><Anti-Rejection Therapy><Antibodies><Antigen Targeting><Antigen-Antibody Complex><Antinuclear Antibodies><Antinuclear Factors><Antirejection Therapy><Attention><Autoantibodies><Autoimmune Diseases><Award><Biological Markers><Blood Serum><Body Tissues><Calcimedins><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Matrix><Cellular Physiology><Cellular Process><Clinical><Cytoskeletal System><Cytoskeleton><Data><Deposit><Deposition><Development><Development Plans><Diagnosis><Dialysis><Dialysis procedure><Discipline><Disease><Disorder><Double-Stranded DNA><Dysfunction><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Evaluation><Exposure to><Extramembranous Glomerulopathy><Filtration><Filtration Fractionation><Functional disorder><Glomerular disease><Goals><Histopathology><Human><IgG><Immune Complex><Immunoglobulin G><Immunosuppressive Therapy><Impairment><Inflammatory><Inflammatory Response><Injections><Injury><K-Awards><K-Series Research Career Programs><Kidney><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Knowledge><Lead><Life><Lipocortins><Lupus><Lupus Erythematosus Disseminatus><Lupus Glomerulonephritis><Lupus Nephritis><Membranous Glomerulonephritis><Membranous Glomerulonephropathy><Membranous Glomerulopathy><Membranous Nephropathy><Mentors><Mentorship><Modern Man><Molecular Marker of Prognosis><Nucleosomes><Pathogenesis><Pathogenicity><Patients><Pb element><Physicians><Physiopathology><Prognosis Marker><Prognostic Marker><Proteins><Proteinuria><Publications><Renal Failure><Renal Glomerular Diseases and Syndromes><Renal Insufficiency><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Research><Research Career Program><Role><SLE><Scientific Publication><Scientist><Serum><Subcellular Process><Systemic Lupus Erythematosus><Systemic Lupus Erythmatosus><Systemic SLE - Lupus Erythematosus><Testing><Therapeutic immunosuppression><Time><Tissues><Training><Treatment Protocols><Treatment Regimen><Treatment Schedule><Validation><Visceral Epithelial Cell><anti-DNA autoantibody><anti-Sm><antiDNA autoantibody><artificial immunosuppression><autoimmune antibody><autoimmune disorder><base><bio-markers><biologic marker><biomarker><career><career development><developmental><diagnostic biomarker><diagnostic marker><dialysis therapy><disease diagnosis><disseminated lupus erythematosus><ds-DNA><dsDNA><experience><experiment><experimental research><experimental study><glomerular visceral epithelial cell><heavy metal Pb><heavy metal lead><immunosuppression therapy><improved><improved outcome><injured><intracellular skeleton><lupus prone mice><membrane-organizing extension spike protein><mesangial cell><model of animal><model organism><moesin><mouse model><murine model><new diagnostics><next generation diagnostics><novel diagnostics><pathophysiology><podocyte><prognostic biomarker><prognostic indicator><programs><public health relevance><renal><response to treatment><self reactive antibody><skills><social role><systemic lupus erythematosis><therapeutic response><treatment response>