The Role of Inflammation and Senescence in Kidney Injury in People with HIV - Project Summary Molly Fisher, DO, MS is establishing herself as a translational investigator in patient-oriented research that focuses on chronic inflammation and senescence as novel contributors to kidney injury in people with HIV. This K23 award will provide the necessary training for Dr. Fisher to successfully transition to an independent physician-scientist and achieve the following goals: (1) develop expertise in urinary extracellular vesicle (EV) phenotyping for detecting early kidney injury and biomarker discovery; (2) gain proficiency in designing and conducting translational studies that leverage prospective cohorts and banked biospecimens; (3) acquire training in advanced biostatistics and bioinformatics approaches for analyzing complex datasets. Dr. Fisher has assembled an exceptional team. Her primary mentor, Dr. Michael Ross, is an established basic science/ translational researcher who uses novel cell lines and animal models to study mechanisms of HIV-associated nephropathy. Her co-mentors include Dr. Christina Wyatt, a leader in HIV kidney disease epidemiology and Dr. Uta Erdbrügger, an expert in urinary EV kidney phenotyping. Dr. Fisher’s advisory team offers complementary expertise in HIV and age-related comorbidity epidemiology, kidney biomarker research, longitudinal data analysis, and multi-omics study design and data analysis. PWH have a significantly higher risk of acute kidney injury (AKI) and chronic kidney disease (CKD) compared to those without HIV. However, mechanisms driving this increased risk in the context of viral suppression are poorly understood. HIV-induced immune activation leads to inflammation and senescence—known contributors to age-related diseases—but these processes are understudied in HIV-related kidney injury. Urinary EVs are released by living kidney cells and carry protein and RNA cargo reflective of their cell of origin, offering noninvasive molecular insights into kidney health. Dr. Fisher’s preliminary findings show that urine EV from PWH with normal kidney function are enriched with inflammatory and senescence cargo, suggesting subclinical injury is present. In this proposal, Dr. Fisher will leverage EV molecular biomarkers to uncover pathways driving kidney injury in PWH—advancing earlier detection and potential targets for therapeutic intervention. In Aim 1, she will establish a cohort of PWH and HIV-negative controls at Einstein-Montefiore and define a subclinical kidney injury phenotype using urinary EV protein and RNA cargo derived from kidney cells. In Aim 2, she will use a prospective HIV cohort from Johns Hopkins to test associations between urine EV biomarkers of inflammation/senescence with incident AKI. This research builds upon Dr. Fisher’s previous work in viral-associated AKI and aligns with her overarching goal of becoming a translational researcher focused on novel mechanisms that contribute to kidney injury in PWH. The resources at Einstein provide an outstanding environment to complete her training and research goals. The proposed studies are feasible within the 5-year award period and, together with the training plan, will position Dr. Fisher to become an independent investigator.
