Targeting Hepatocyte Senescence to Improve NAFLD

Non-alcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease, and its incidence and prevalence are expected to worsen with the growing aging population and epidemics of obesity and metabolic syndrome. Unfortunately, NAFLD pathogenesis remains poorly understood and an effective pharmacotherapy is lacking. Recent studies demonstrated that senescent hepatocytes accumulate in human NAFLD and correlate with adverse outcomes. However, the characteristics of senescent hepatocyte have not been defined, and it is unclear what molecular mechanisms drive/maintain this senescent phenotype or if/how the senescent phenotype per se effects NAFLD progression. My preliminary data from NAFLD patients, rodent NAFLD models and cultured senescent hepatocytes strongly suggest that hepatocyte senescence is involved in NAFLD pathogenesis and drives NAFLD progression. I hypothesize that preventing accumulation of senescent hepatocytes will improve NAFLD, and will test this hypothesis by pursuing three specific aims: Aim 1: Define the transcriptome, secretome and paracrine effects of senescent hepatocytes. Aim 2: Dissect the molecular mechanisms of hepatocyte senescence. Aim 3: Determine the role of hepatocyte senescence in NAFLD pathogenesis/progression. Overall, this project will evaluate a clinically relevant, innovative and impactful hypothesis by employing multiple state-of-the-art approaches (i.e. CRISPR-based screening, bioactive chemical screening, genome editing, single nuclei RNA-Seq, secretomics, etc) to comprehensively characterize the hepatocyte senescent phenotype, uncover fundamental mechanisms that regulate senescence-associated liver biology (e.g. phenotypic heterogeneity, metabolic reprogramming and state transitions) and identify novel senolytic therapies for NALFD. Successful completion of this study will provide novel molecular mechanisms for NAFLD pathogenesis and thus, establish the groundwork for future projects that exploit cellular senescence as a novel strategy to treat NAFLD and other liver diseases. Together with the comprehensive career development plan outlined herein, this project will advance my expertise in several areas, including cellular senescence, bioinformatics, secretomics, high- throughput screenings and genome editing. A seasoned mentoring team with diverse and complementary expertise, lengthy track records for training research scientists and full commitment for mentorship is established, and will guide my career development by providing mentorship and research resources, and offering professional scientific training during the award period. This award will provide me with superb professional and scientific skillsets, enabling me to be a very competitive and worthy applicant for independent academic faculty positions and future R01 applications.