This proposal describes a comprehensive 5-year training program designed to foster the continued development of a career in academic medicine. Dr. Leventhal has completed residency in Internal Medicine (Univ. of Chicago), Fellowship in Nephrology (Mount Sinai School of Medicine), and spent the last years gaining basic science research experience. The current application is structured to transition Dr. Leventhal from trainee to independent investigator by leveraging intellectual and material resources available at Mt. Sinai. Dr. Ross, who has already mentored several successful trainees, will guide Dr. Leventhal throughout his training. Dr. Ross is the Fellowship Program Director for the Division of Nephrology, an established NIH-funded independent investigator and a recognized leader in the field of HIV-associated renal disease. Dr. Yue, an expert in the field of autophagy, an NIH-funded investigator, and an accomplished mentor in his own right, will serve as co-mentor. An advisory committee composed of highly regarded and successful principal investigators will provide additional counsel on both scientific and career issues. Dr. Leventhal's career development plan is comprehensive, including frequent meetings with his mentor, meetings with his advisory committee and enrolling in classes early in his traineeship to improve his knowledge base of molecular/cell biology signal transduction, immunology, scientific ethics, and grant preparation. Dr. Leventhal will attend seminars and national conferences where he will present his research, establish collaborations, and learn of recent advances in his field. Dr. Leventhal's research utilizes state-of-the-art molecular methods to advance understanding of the pathogenesis of septic acute kidney injury (AKI), a common and devastating clinical problem. In this application, he proposes to study how autophagy affects the pathogenesis of septic AKI using a human renal tubular epithelial cell (RTEC) line and a novel murine model. Autophagy is an intracellular process that results in the degradation of sequestered cytoplasmic elements. Autophagy is known to impact many human diseases but whether it modulates septic AKI is unknown. In the first specific aim, he will determine how suppression of autophagy gene expression and pharmacological autophagy inhibition affect RTEC injury after LPS exposure. In the second specific aim, the signaling pathways responsible for autophagy induction in LPS exposed RTEC will be determined using pathway specific inhibitors and protein analysis. In the third aim, he will determine whether conditional knockout of autophagy in the proximal tubule worsens renal injury following LPS injection. These will be the first in vivo studies to evaluate how autophagy modulates septic AKI. The Mount Sinai Division of Nephrology is an ideal training environment for physician investigators where Dr. Leventhal will receive outstanding mentoring, extensive education, and strong institutional support, providing him with the best possible opportunity to cultivate a successful career as a physician investigator.
Sepsis-induced acute kidney injury (AKI) is a devastating complication, with profoundly negative short-term and long-term health implications, for which no strategies or therapeutic interventions exist. New targets for pharmaceutical intervention are desperately needed to improve the clinical outcomes of patients with this devastating disease. The proposed research evaluates if renal autophagy modifies the severity of lipopolysaccharide-induced AKI and would be a target for future pharmacological interventions.
|Leventhal, Jeremy S; Ni, Jie; Osmond, Morgan et al. (2016) Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression. PLoS One 11:e0150001|
|Leventhal, Jeremy S; He, John C; Ross, Michael J (2014) Autophagy and immune response in kidneys. Semin Nephrol 34:53-61|