Role of DNAJC22 in Steatotic Liver Disease

About This Grant

Project Summary Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging health epidemic in the United States with few therapeutic options. The accumulation of lipid droplets within hepatocytes drives the pathogenesis of MASLD, yet the cellular mechanisms governing lipid storage in lipid droplets remain incompletely understood. My goal is to address this knowledge gap and advance the development of new therapies for MASLD. My preliminary work integrated genome-wide CRISPR-Cas9 screening and human genetic association studies to identify DNAJC22, a gene of unknown function, as a novel regulator of lipid droplet accumulation. Knockout of DNAJC22 dramatically reduced lipid droplet accumulation, and overexpression of DNAJC22 led to the accumulation of giant lipid droplets in hepatocytes. I also identified a predicted loss-of-function mutation in DNAJC22, p.A163T (rs146774114) that was associated with protection from MASLD across multiple human genetic biobanks. This application will explore DNAJC22 as a potential new therapeutic avenue for the treatment of MASLD. I will evaluate the cellular pathways through which DNAJC22 promotes lipid droplet accumulation and assess the impact of silencing DNAJC22 in preclinical models of MASLD. In Aim 1, I will quantify the effects of DNAJC22 overexpression, knockout, and the p.A163T variant on lipolysis, beta oxidation, and lipoprotein export pathways in human hepatoma cells and human precision-cut liver tissue slices (PCLS). In Aim 2, I will evaluate the in vivo effects of therapeutic hepatocyte- directed silencing of DNAJC22 on disease activity and fibrosis progression in two murine models of MASLD and tie these effects to alterations in neutral lipid flux. My long-term objective is to become an independent laboratory investigator that uses human genetics, functional assays, and translational disease models to define the molecular basis of MASLD. In this mentored research career development proposal, I will learn metabolic assays to dissect lipid droplet biology, acquire skills in state-of-the-art genome engineering techniques, and learn translational models of MASLD. The primary mentor of this application, Dr. Rajat Gupta, is a leader in functional genomics, and the co-mentor Dr. Jean Schaffer is a leader in MASLD and metabolism; both have exceptional track records of mentorship. A decidated advisory committee will provide training in metabolism (Dr. David E. Cohen), genome engineering (Dr. John Doench), murine MASLD models (Dr. Yury Popov), and PCLS (Dr. Gordon Jiang) and contribute scientific input and additional career guidance. This application is coupled with the full support of Beth Israel Deaconess Medical Center and the outstanding educational resources at the Broad Institute, Harvard Medical School, and affiliated institutions.