This Project Grant award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) provides $396,750 to the University of Pittsburgh to conduct a mechanistic study on pegylated asparaginase (PEG-asparaginase)-induced liver injury. The research aims to: 1) Demonstrate that inhibition of adipose triglyceride lipase (ATGL)-mediated white adipose tissue lipolysis can attenuate PEG-asparaginase-induced liver injury, 2) Show that PEG-asparaginase-responsive ATGL activation and liver injury are mediated by GCN2-dependent induction of cathepsin S, and 3) Investigate whether PEG-asparaginase-induced upregulation of CYP2E1 sensitizes hepatocytes to lipotoxicity. The long-term goal is to identify approaches to enable the safe use of PEG-asparaginase and extend its therapeutic benefit to adult acute lymphoblastic leukemia patients. The award period runs from September 1, 2024 to June 30, 2028.
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