This career development award supports the development of Sevgi Gurkan, MD as an independent researcher with a primary focus on immunological mechanisms of proteinuria. Dr. Gurkan is a pediatric nephrologist and a junior investigator with significant past training in immunology. She has assembled an outstanding multidisciplinary team of mentors and advisory committee members to guide her research career development. Dr. Gurkan's short term career goals include enhancing her knowledge in mouse models of disease, acquiring new cellular biology skills and expanding her experience in clinical research and molecular genetics through mentoring, advanced training and supervised research experience set forth in this K08 proposal. The Rutgers University and Harvard Medical School offer outstanding resources and mentorship that will enable Dr. Gurkan to achieve her long term goal of transitioning into an independent investigator. In this application, Dr. Gurkan proposes to study the mechanism of toll like receptor (TLR) ligand induced proteinuria in the context of childhood nephrotic syndrome (NS). Despite being a leading cause of end-stage kidney disease among children, the etiology of NS remains largely unknown. Mutations in several podocyte genes can be identified in up to 30% of NS patients. In the remainder, abnormal immune activity has been implicated, based on viral or bacterial infections preceding NS relapses and disease response to immunomodulator treatment. However, how abnormal immune activity leads to NS is an open question. The goals of this proposal are: 1) to explore the contribution of systemic TLR activation to proteinuria, 2) to determine the mechanism of TLR ligand induced proteinuria and 3) to investigate the activity of TLR signaling in patients with childhood NS. This proposal provides a novel mechanism for the pathogenesis of proteinuria. Validation of the study hypothesis will pave the way for new therapeutics resulting in better and more individualized therapies which will improve future patient outcomes.
Nephrotic syndrome (NS) remains to be a leading cause of renal failure necessitating dialysis among children. Even the mildest form of NS is characteristically a recurrent disorder that increases disease- and treatment- associated complications making it a significant health problem in the pediatric and adult populations. The proposed studies provide a unique opportunity to develop a more comprehensive understanding of NS pathogenesis that will result in the development of better and individualized therapies to improve future patient outcomes.