A chemogenomic approach to target identification in primary human NASH models

• Applicant: Dr. Sabine Willems
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry ; Gastroenterology ; Pharmacology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533772148

Non-alcoholic steatohepatitis (NASH) is a serious liver disease characterized by fat accumulation, inflammation, and fibrosis. It affects ~6% of the global population but lacks effective treatment options and is thus a severe medical and healthcare challenge. Pharmacological treatment options are urgently needed to address this unmet medical need. Therapeutic modulation of nuclear receptors (NRs), many of which crucially regulate hepatic metabolism and inflammation, is increasingly recognized as potential avenue to hepatoprotective NASH treatment. However, only a minor fraction of the 48 human NRs has been evaluated in this context and comprehensive understanding of the entire NR family’s involvement in NASH pathology is lacking. Growing evidence supports remarkable potential of many (orphan) NRs to mediate beneficial therapeutic effects in NASH. For example, relevant sex-specific differences in NASH incidence point to an involvement of steroid hormones which act via NR activation. The role of hormone sensing and other NRs in the disease complex urgently requires systematic and comprehensive evaluation for therapeutic potential. This project aims to close this gap by systematically probing NR modulation for therapeutic effects in a primary patient-derived tissue model following a chemogenomics (CG) strategy. To meet its main objective of achieving comprehensive understanding of the pharmacological role of NRs in NASH, the project will assemble a custom CG compound set to cover ≥40 of the 48 human NRs and systematically assess the phenotypic outcomes of NR modulation in liver spheroids generated from primary human hepatocytes and non-parenchymal liver cells. Using such sophisticated in vitro model to mimic relevant disease characteristics aims to overcome incomplete translation from rodent model to patient in NASH and to capture individual and sex-specific differences. Primary evaluation will focus on anti-steatotic, anti-inflammatory, anti-fibrotic, and anti-oxidative effects in a global, sex-specific, and genotype-dependent manner. Subsequently, beneficial effects resulting from NR modulation will be orthogonally validated and analyzed in-depth for sex- and patient-specific roles, dependence on metabolic parameters, potential synergies of dual modulation, and signaling networks. This unprecedented systematic and comprehensive approach to explore NRs as therapeutic targets for NASH treatment will reveal uncharted potential of this protein family and address an urgent unmet medical need. Additionally, new insights into the roles of steroid hormones as well as sex- and patient-specific differences in NASH will offer significant biological advance and may suggest personalized treatment strategies.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Dr. Volker Lauschke