Tuesday, February 4, 2025
2/4/2025
PROJECT SUMMARY In the US, 42.4% of the adults are classified as obese. Obesity associated metabolic diseases, including type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD) and its progressive stage nonalcoholic steatohepatitis (NASH), severely impact human quality of life and mortality. Current anti-obese and diabetic drugs are often associated with different side effects, and currently there are no Food and Drug Administration (FDA) approved drugs for NAFLD/NASH. The long-term goal is to meet this critical unmet need for innovative novel pharmacological therapies with improved safety profiles and durable treatment effects for obesity and its complications. Bile acids (BAs) play important roles in regulating lipid, glucose, and energy metabolism. CYP8B1, is exclusively expressed in the liver and it functions specifically to control the ratio of 12α- hydroxylated (OH)/non-12α-OH BAs in the-BA pool. CYP8B1 deficiency leads to reduction 12α-OH)/non-12α- OH BAs ratio, resulting in metabolically beneficial effects including weight loss, ameliorated fatty liver and inflammation, with insulin sensitivity, in mice and humans. The central hypothesis is that CYP8B1-specific inhibitors may provide a unique pharmacological approach to treat obesity and related metabolic diseases. The rationale for the proposed research is that no CYP8B1-specific inhibitors exist and the lack of high-throughput screening (HTS) methods hinders the identification of CYP8B1-specific inhibitors. The objective of this grant application is to develop strategies for CYP8B1 inhibition by identifying potent CYP8B1-specific inhibitors to pharmacologically alleviate metabolic disorders in mouse disease models. We have established a high- throughput screening (HTS) platform to identify and optimize CYP8B1-specific inhibitors with potent in vivo efficacy in metabolic disease models toward drug development. The HTS was implemented for a ~45,000- compound library that led to the identification of potent, specific CYP8B1 inhibitors with biochemical and functional validation. Most importantly, we found that a lead CYP8B1 inhibitor compound that displayed strong efficacy in inhibiting CYP8B1 in vivo. The novel HTS-assay and the identified candidate CYP8B1-inhibitors will be used to test two Specific Aims: 1) identification and characterization of CYP8B1-specific inhibitors; and 2) Determination of CYP8B1-specific inhibitor therapeutic effects in metabolic disease models. The completion of this grant proposal will help us generate first-in-class candidates for drug development. The results will positively impact efforts to improve obesity, T2D and NAFLD/NASH clinical outcomes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).