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Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression

Award Number: R01DK119421
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Non-alcoholic fatty liver disease (NAFLD) develops as a result of fat deposited into the liver (steatosis) caused by other factors aside from alcohol; and, NAFLD is now the most common liver disease in Western developed countries. If left untreated or if another insult occurs (“two-hit” hypothesis), NAFLD can develop into NASH. While hepatocytes are believed to be the primary cell involved in NAFLD, new studies have demonstrated that both cholangiocytes and mast cells (MCs) contribute to NAFLD progression and potentially to NAFLDèNASH transition. Further, damaged cholangiocytes undergo senescence and take on a senescence-associated secretory phenotype (SASP), which may also contribute to the inflammatory environment seen in NASH. MCs are found in adipose tissue of obese patients and histamine levels are increased in patients with NAFLD, NASH and end-stage liver disease. To date, no successful treatments have been developed for NAFLD, aside from altering diet and lifestyle; and, there have been no studies to examine the potential paracrine interaction between cholangiocytes and MCs in models of NAFLD. Further, the synergistic relationship between MCs, cholangiocytes, hepatic stellate cells (HSCs) and Kupffer cells has not been fully examined. The premise of the study is supported by: (i) previous work demonstrating that both cholangiocytes and MCs contribute to NAFLD; (ii) work from the PI demonstrating that MCs contribute to liver damage and are critical regulators of disease progression; and, (iii) preliminary data showing that there is a direct interaction between cholangiocytes and MCs that influences hepatic damage, Kupffer cell activation/inflammation and HSC-driven fibrosis during NAFLD. In SA1, the PI will examine biliary-induced MC migration using mice subjected to HFD/HFCS and Vivo-Morpholino treatments to inhibit biliary senescence. This aim will focus primarily on the interactions between cholangiocytes and MCs. SA2 will focus on the contribution of MCs to NAFLD progression by using a genetic model of MC depletion and also reintroduction of MCs. These studies allow us to examine the effects of losing MCs, but also to determine if MCs perpetuate NAFLD progression and potentially NAFLD to NASH transition (marked by enhanced liver inflammation). Finally, in SA3, the PI will focus on the inhibition of MC-derived histamine and TGF-b1 using pharmaceutical inhibition to directly target this inflammatory molecule. Preliminary data and previous publications reveal that TGF-b1 may be a key modulator of NAFLD and liver damage (including fibrosis); and, MC-derived histamine regulates TGF-b1 expression and secretion. In all of proposed aims, the PI will evaluate NAFLD induced by both Western Diet (HFD/HFCS) and the methionine-choline deficient (MCD) diet. In addition, features of metabolic syndrome including insulin resistance, elevated triglycerides, lipoprotein abnormalities, and glucose intolerance will be evaluated. Targeting MC mediators may be a beneficial therapeutic approach to managing NAFLD progression.!


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: 2025 ( Subtotal = -$93,179 )
2025	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	10/16/2024	NON-COMPETING CONTINUATION	-$93,179
														Subtotal = -$93,179

Issue Date FY: 2022 ( Subtotal = $352,325 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/5/2022	NON-COMPETING CONTINUATION	$352,325
														Subtotal = $352,325

Issue Date FY: 2021 ( Subtotal = $352,529 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/24/2021	NON-COMPETING CONTINUATION	$352,529
														Subtotal = $352,529

Issue Date FY: 2020 ( Subtotal = $374,589 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/22/2020	NON-COMPETING CONTINUATION	$352,724
2020	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/9/2020	NEW	$21,865
														Subtotal = $374,589

Issue Date FY: 2019 ( Subtotal = $331,045 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/23/2019	NEW	$331,045
														Subtotal = $331,045

Grand Total All Awards = $1,317,309

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Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression

Award Number: R01DK119421

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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