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Regulation of the pro-fibrotic connective tissue growth factor in alcoholic liver disease: mechanisms and targeting approaches

Award Number: R01AA028035
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary / Abstract: Alcoholic liver disease is a major health and financial concern worldwide. Liver fibrosis and its advanced form, cirrhosis, can occur in virtually all types of chronic liver disease (CLD) including alcohol-induced liver injury. According to the American Liver Foundation, 5.5 million Americans are currently afflicted with CLD or cirrhosis, and the National Institutes of Health (NIH) reports cirrhosis as the 12th leading cause of death due to disease in America. Hepatic progenitor cells (HPCs) are the source of an alternative regenerative mechanism when hepatocyte proliferation is inhibited due to severe liver damage. HPC are closely associated with activated myofibroblast cells (MF) and correlate with severity of liver fibrosis in many CLD. No FDA approved treatment is currently available for any fibrotic disorder. There is an urgent need for the development of anti-fibrotic drugs to control progression of fibrosis while in reversible stages. Connective tissue growth factor (Ctgf) is a profibrotic mediator and modulates cell-cell and cell-matrix signaling through binding to a variety of growth factors, matrix protein, and cell surface proteins including integrins. It is a target gene of the transcriptional coactivator Yes-associated protein (Yap) and acts as an enhancer of transforming growth factor (Tgf)-ß, promoting liver fibrosis and HPC activation in chronic liver disease. Our studies demonstrated fine-tuned regulation of Ctgf via hepatocyte nuclear factor (Hnf)4a antagonism of Yap and TGF-ß1 signaling in regenerating hepatocytes whereas Ctgf deficiency reduces hepatic inflammation, hepatocyte proliferation and collagen synthesis. Adamts7 (a disintegrin and metalloproteinase with thrombospondin type I repeat 7) was identified as a novel enzyme for Ctgf turnover during liver injury. The Ctgf binding protein-extracellular matrix protein (ECM)1- was identified to inhibit Tgf-ß activation and exhibited anti-fibrotic potential. The multifaceted regulations of Ctgf during fibrosis offers important translational opportunities for diagnosis and follow-up of hepatic fibrogenesis as well as intriguing targets for therapeutic interventions. Utilizing a noninvasive imaging technique we recently developed, in Aim 1, the function of Adamts7 in regulating fibrotic responses during alcohol-induced liver injury will be examined. In Aim 2, the anti-fibrotic effects of ECM1 on alcoholic liver injury and HPC activation will be assessed. This study will provide new mechanistic insights during alcoholic liver disease. The knowledge we obtain will help identify molecular targets to enhance liver regeneration and reduce liver 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: 2024 ( Subtotal = $299,870 )
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Alcohol Research Programs	000	6	1/31/2024	NON-COMPETING CONTINUATION	$299,870
														Subtotal = $299,870

Issue Date FY: 2023 ( Subtotal = $333,189 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Alcohol Research Programs	000	5	1/18/2023	NON-COMPETING CONTINUATION	$333,189
														Subtotal = $333,189

Issue Date FY: 2022 ( Subtotal = $333,189 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Alcohol Research Programs	003	4	6/22/2022	NON-COMPETING CONTINUATION	$33,319
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Alcohol Research Programs	002	4	1/24/2022	NON-COMPETING CONTINUATION	$299,870
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Alcohol Research Programs	001	3	12/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$49,974
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Alcohol Research Programs	000	2	12/10/2021	NON-COMPETING CONTINUATION	-$49,974
														Subtotal = $333,189

Issue Date FY: 2021 ( Subtotal = $343,934 )
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Alcohol Research Programs	002	3	9/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$233,494
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Alcohol Research Programs	001	2	9/19/2021	NON-COMPETING CONTINUATION	-$233,494
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Alcohol Research Programs	000	2	2/19/2021	NON-COMPETING CONTINUATION	$343,934
														Subtotal = $343,934

Issue Date FY: 2020 ( Subtotal = $355,747 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Alcohol Research Programs	000	1	1/28/2020	NEW	$355,747
														Subtotal = $355,747

Grand Total All Awards = $1,665,929

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Regulation of the pro-fibrotic connective tissue growth factor in alcoholic liver disease: mechanisms and targeting approaches

Award Number: R01AA028035

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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