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The transcription factor RUNX1 is pivotal in TGFβ-activated cholangiocyte signaling with the immune system in biliary fibrosis

Award Number: K08DK140618
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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The transcription factor RUNX1 is pivotal in TGFβ-activated cholangiocyte signaling with the immune system in biliary fibrosis - PROJECT SUMMARY/ABSTRACT Primary sclerosing cholangitis (PSC) and primary biliary cholangitis are characterized by biliary fibrosis, which involves activated cholangiocyte signaling with immune cells. Insufficient understanding of the transcriptomic and lipidomic changes in activated cholangiocytes that orchestrate signaling with the immune cells is a major barrier for developing effective therapies for biliary fibrosis. Transforming growth factor-β (TGFβ), a key mediator of fibrosis, activates cholangiocytes to produce fibroinflammatory signals. Our preliminary data show that Runt- related transcription factor 1 (RUNX1) expression is increased in models of biliary fibrosis and PSC livers. RUNX1 inhibition reduces the upregulation of fibroinflammatory signals in TGFβ-activated and PSC-derived cholangiocytes. RUNX1 inhibition in a mouse model of biliary fibrosis reduces the hepatic peri-portal infiltration of immune cells and markers of hepatic injury. The effects of RUNX1 may be further facilitated by its upregulation of stearoyl-CoA desaturase-1 (SCD1) and lipid signaling. Treatment with an SCD1 inhibitor, Aramchol – an agent with a well-established safety profile in clinical trials – results in reduced fibroinflammatory markers in mouse models of biliary fibrosis. Therefore, we hypothesize that RUNX1 plays a crucial role in the activation of cholangiocytes by coordinating an interdependent transcriptomic and lipidomic program that stimulates immune cells. To test this novel hypothesis, we propose two specific aims. In aim 1, we will investigate RUNX1 co-regulators of gene expression and the full spectrum of RUNX1-dependent fibroinflammatory pathways in TGFβ-activated cholangiocytes. Using a biliary epithelial-specific Cre, we have generated cholangiocyte- selective Runx1 genetic deletion to study immune cell recruitment and activation, and fibrosis in mouse models of biliary fibrosis. We will also determine the direct effects of cholangiocyte RUNX1-induced signals on macrophage activation and Th17 cell differentiation using in vitro co-culturing of primary cells and spatial transcriptomic and single cell RNA-seq analyses of PSC and mouse model livers. In aim 2, we will determine if TGFβ-RUNX1 signaling directly regulates SCD1 expression and function, and effects on cholangiocyte fibroinflammatory lipidomics. The effects of SCD1 on cholangiocyte lipidomics and fibroinflammatory signals will be investigated in mouse models of biliary fibrosis using Aramchol and Scd1 genetic deletion. TGFβ-induced transcriptomic and lipidomic changes in cholangiocytes will be integrated to better define the roles of RUNX1 and SCD1. Further elucidation of these transcriptomic and lipidomic regulatory mechanisms will advance our grasp of biliary fibrosis and support the development of effective therapies. Therefore, our proposal is consistent with the objectives of NIDDK in understanding and developing therapeutic avenues for hepatobiliary diseases. Additionally, this proposal will allow a promising physician-scientist to gain expertise in the epithelial immunology, lipidomics, and transcriptomics of biliary fibrosis under the expert guidance of highly dedicated mentors to successfully transition to an independently funded physician-scientist with a unique research program.


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 = $176,148 )
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/29/2026	NON-COMPETING CONTINUATION	$176,148
														Subtotal = $176,148

Issue Date FY: 2025 ( Subtotal = $176,094 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/11/2025	NEW	$176,094
														Subtotal = $176,094

Grand Total All Awards = $352,242

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The transcription factor RUNX1 is pivotal in TGFβ-activated cholangiocyte signaling with the immune system in biliary fibrosis

Award Number: K08DK140618

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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