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Molecular Mechanisms of Cholestatic Fibrogenesis

Award Number: R01DK117861
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Molecular Mechanisms of Cholestatic Fibrogenesis - PROJECT SUMMARY / ABSTRACT Cholestatic fibrogenesis is a pathobiological process of the bile ducts, characterized by biliary strictures, cholestasis, and progressive peri-portal fibrosis. During biliary fibrosis, diseased cholangiocytes become highly secretory, releasing a variety of paracrine signaling molecules that subsequently activate hepatic stellate cells (HSC). Progression toward end stage disease is characterized by an exaggerated fibrogenic response to chronic injury, culminating in peri-portal deposition of matrix molecules that progresses to biliary cirrhosis. We have also shown that the cholangiocyte secretome, which mediates the crosstalk, depends heavily on regulatory mechanisms involving epigenetic enzymes and long non-coding RNAs (lncRNAs) to modify chromatin. The ensuing histone modifications in cholangiocytes drive transcription of pathological gene networks that perpetuate fibrosis. The novel direction described here supports the concept that TGF-β induced lncRNAs in cholangiocytes can serve either as decoy lncRNAs to prevent engagement of chromatin silencers (e.g., enhancer of zeste homologue 2, EZH2) or as guide lncRNAs to engage chromatin activators (e.g., lysine acetyl transferase 2A, KAT2A). We have generated the following novel preliminary data: i) Pathologic TGF-β signaling induces upregulation of 267 lncRNAs in cholangiocytes, including TILC and TGFB2-AS1; ii) A network of cholangiocyte-derived paracrine activators of HSCs are regulated by histone modifiers and lncRNAs as demonstrated by chromatin immunoprecipitation sequencing (ChIP-seq), RNA-sequencing (RNA-seq) and RNA immunoprecipitation (RIP); iii) Biliary organoids derived from MDR2 knockout (KO) mice demonstrate distinct upregulation of lncRNAs; and iv) Biliary fibrosis is exacerbated in EZH2 KO mice and blunted in KAT2A KO mice. Based on this preliminary data, we propose the central hypothesis that dysregulated cholangiocyte lncRNAs orchestrate the cholangiocyte epigenome to amplify production of a fibrogenic secretome. In Aim I, we will test the subhypothesis that a decoy lncRNA prevents gene silencing by excluding EZH2 from chromatin. In Aim II, we will evaluate the subhypothesis that a guide lncRNA recruits KAT2A to chromatin to promote a fibrogenic secretome. In Aim III, we will investigate the subhypothesis that targeting specific lncRNAs will prevent fibrogenesis in mouse models and human organoids. In summary, we propose the novel concept that lncRNA dysregulation influences key epigenetic regulators in cholangiocytes to modify chromatin and drive transcription of a fibrogenic gene network. Interventions targeting these newly discovered pathways with RNA therapeutics may have the capability to prevent or reverse specific molecular events that underlie biliary fibrosis.


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 = $351,045 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	12/30/2025	NON-COMPETING CONTINUATION	$351,045
														Subtotal = $351,045

Issue Date FY: 2025 ( Subtotal = $351,045 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	1/23/2025	NON-COMPETING CONTINUATION	$315,941
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	5/14/2025	NON-COMPETING CONTINUATION	$35,104
2025	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $351,045

Issue Date FY: 2024 ( Subtotal = $351,045 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	12/21/2023	COMPETING CONTINUATION	$351,045
														Subtotal = $351,045

Issue Date FY: 2023 ( Subtotal = $357,750 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/20/2023	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2022 ( Subtotal = $357,750 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/4/2022	NON-COMPETING CONTINUATION	$35,775
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/21/2022	NON-COMPETING CONTINUATION	$321,975
														Subtotal = $357,750

Issue Date FY: 2021 ( Subtotal = $357,750 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/2/2021	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2020 ( Subtotal = $357,750 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/10/2020	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2019 ( Subtotal = $357,750 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/7/2019	NEW	$357,750
														Subtotal = $357,750

Grand Total All Awards = $2,841,885

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Molecular Mechanisms of Cholestatic Fibrogenesis

Award Number: R01DK117861

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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