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.