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Metabolism-mediated epigenetic regulation of hepatic stellate cell activation during liver fibrosis

Award Number: F31DK146505
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/31/2026
PERIOD OF PERFORMANCE END DATE: 03/30/2029

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Metabolism-mediated epigenetic regulation of hepatic stellate cell activation during liver fibrosis - PROJECT SUMMARY/ABSTRACT Cirrhotic stage liver disease is the 9th leading cause of mortality in the US, and no treatment exists for late-stage disease other than liver transplantation. Thus, the overall objective of this proposal is to elucidate novel mechanisms that drive liver fibrosis progression and to guide the development of potential treatment strategies. Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Our preliminary data in primary human and mouse HSCs as well as in vivo demonstrate that 1. Platelet derived growth factor (PDGF) increases acetyl-CoA levels in HSCs and the expression of one of the histone acetyltransferases, lysine acetyltransferase 2B (KAT2B); 2. PDGF-mediated glycolysis increases the epigenetic transcription activation mark, histone 3 lysine 9 acetylation (H3K9ac) in HSCs; 3. In vitro pharmacological inhibition of H3K9ac by CPTH6 prevents proliferation and migration of PDGF-stimulated HSCs; 4. In vivo drug inhibition of H3K9ac by CPTH6 reduces liver fibrosis; 5. H3K9ac levels and KAT2B expression are increased in mice fibrotic livers. We utilized our novel findings to generate the CENTAL HYPOTHESIS of the current proposal that Glycolysis-mediated H3K9ac by KAT2B promotes HSC activation and liver fibrosis. We will employ sophisticated cellular and animal models, including in vitro carbon-13 glucose tracing, chromatin immunoprecipitation sequencing (ChIP-seq), in vitro utilization of dCas-KRAB model, in vivo HSC-specific KAT2B deletion model as well as an ex vivo liver fibrosis model with human precision cut liver slices (PCLS), to investigate the following integrated, yet independent aims. In Aim 1, we will test the hypothesis that glycolysis derived acetyl-CoA promotes H3K9ac dependent pro- fibrogenic gene expression. We will uncover the gene programs regulated by glycolysis- linked H3K9ac in HSCs by: a. studying how glucose metabolism contributes to the production of acetyl-CoA, the main metabolite to acetylate the histones, and how this affects H3K9ac; and b. investigating how investigating the gene promoters in PDGF-stimulated HSCs that are enriched with H3K9ac. In Aim 2, we will test the hypothesis that KAT2B- dependent H3K9ac and subsequent HSC activation induce liver fibrosis. We will dissect how HSC-specific H3K9ac amplifies liver fibrosis by: a. studying how KAT2B, the acetyltransferase responsible for H3K9ac, impacts HSC activation in vitro, including proliferation and migration; and b. examining how H3K9ac amplifies ex vivo and in vivo liver fibrosis. This novel and innovative line of inquiry will define an HSC-specific glycolysis- dependent model of liver fibrosis amplification and set a trajectory towards new and significant advances to treat liver fibrosis and cirrhosis in humans. Lastly, completing the planned education outlined in goals for fellowship training and this project will contribute to my overall formation as an independent scientist with a career in advancing the research for digestive health.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $49,538 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/31/2026	NEW	$0
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/31/2026	NEW	$49,538
														Subtotal = $49,538

Grand Total All Awards = $49,538

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Metabolism-mediated epigenetic regulation of hepatic stellate cell activation during liver fibrosis

Award Number: F31DK146505

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/31/2026

PERIOD OF PERFORMANCE END DATE: 03/30/2029

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