Abstract Primary membranous nephropathy (MN) is a major cause of nephrotic syndrome and kidney diseases. This autoimmune condition is characterized by the accumulation of immune complexes along the glomerular basement membrane (GBM). What triggers autoantibody production and its contribution to organ damage in MN remains incompletely understood. As such, further understanding of these pathological events could enable timely diagnosis and an overall improvement of treatment outcome in MN. Our previous interdisciplinary proteomic approach identified the serine protease HTRA1 as a novel autoantigen in MN. In this “Mentored Clinical Scientist Research Career Development (K23) Award”, mechanistic studies will be implemented to identify the precise pathogenic HTRA1 epitopes targeted by autoantibodies and their impact on HTRA1 protein function (Aim 1). Furthermore, contributions of HTRA1 autoantibodies as well as HTRA1 antigen accumulation to disease development will be investigated in newly developed animal models of MN (Aim 2). This five-year proposal aims to support the transition of the candidate from a junior physician scientist to an independent investigator in nephrology under the mentorship of leading experts in immunology, nephrology, and other relevant fields (Drs. Haecker, Beck, and Hageman). Building upon the candidate’s strong clinical experience (running the glomerular disease clinic at the University of Utah and utilizing biospecimens from the national MN clinical research network of CureGN, ARUP, and Arkana laboratories) and prior research exposure in glomerular disease, various intensive training modules will be designed to refine his scientific knowledge. Career development training will also be implemented to prepare the candidate with the necessary communication and leadership skills to become an independent investigator. Lastly, access to ample resources to support the aforementioned scientific studies and educational programs will ensure a timely successful execution of this proposal, allowing the candidate to begin his career path of scientific independence.

Project Narrative Membranous nephropathy (MN) is a kidney disease that results from an autoimmune response against the kidney glomeruli. Recently, HTRA1 has been identified as a new antigen in MN. Currently, little is known about the mechanisms by which HTRA1 may trigger autoimmune responses in this disease. This proposal will employ an integrated approach of proteomics and animal studies to characterize HTRA1 epitopes, which might be involved in MN development. The study should extend and expand insights regarding the disease mechanisms of HTRA1- associated MN, as well as establishing a foundation to develop novel peptide-based therapies for this condition.