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Molecular Mechanisms of Liver Fibrosis

Award Number: R37AA021171
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Molecular Mechanisms of Liver Fibrosis - Hepatic stellate cell (HSC) activation encompasses aphenotype that includes enhanced migration, proliferation, and matrix deposition. Migration is critical for coordinately situating HSC for matrix deposition and development of cirrhosis. Our Long-Term Objectives are to understand the molecular underpinnings of HSC biology that lead to cirrhosis with the goal of identifying therapeutic targets. Recently,we identified a critical role of synectin in the process of HSC migration and fibrosis. Synectin is a cytosolic protein that mediates signal transduction, vesicle trafficking, and ultimately gene expression. Synectin is chosen for this proposal as a significant protein warranting detailed investigation because, as we demonstrate, it is upregulated in human cirrhosis and is required for murine fibrogenesis. Mechanistically, we implicate synectin inHSC migration through both short term receptor signaling as well as longer term epigenetic regulation of gene expression networks. Our preliminary data show that depletion of HSC synectin reduces migration signaling downstream of the receptor tyrosine kinase, platelet derived growth factor receptor alpha (PDGFRα); attenuates transcription of a set of HSC activation genes including one that encodes the multifunctional signaling protein, IGFBP3 (insulin growth factor binding protein-3); and abrogates murine fibrosis in vivo. These important observations have led us to propose the central hypothesis that synectin increases HSC migration and fibrosis by promoting PDGFRα signaling and by regulating a network of genes that include IGFBP3. This hypothesis leads to the following Specific Aims: 1) Synectin promotes HSC migration by regulating PDGFRα targeting and signal activation. Aim 1a will determine how synectin recruits and binds specific vesicle trafficking proteins that maintain PDGFRα protein levels, target the protein to endosomes and activate migration signaling. Aim 1b will uncover how disruption of synectin function leads to autophagic degradation of PDGFRα and attenuated HSC migration. 2) Synectin epigenetically controls IGFBP3 gene expression to promote HSC migration. Aim 2a will identify how synectin regulates a specific histone methyl transferase, EZH2 and how this governs IGFBP3 gene expressionthrough histone methylation. Aim 2b will determine how IGFBP3 production stimulates HSC migration. 3) Synectin regulates fibrosis in vivo. Aim 3a will use a novel fibrosis regression model in mice with HSC selective modifications to synectin and PDGFRα to further ascertain the proposed role of these proteins in vivo. Aim 3b will use a synectin neutralizing peptide that selectively targets HSC in coordination with magnetic resonance elastography (MRE) imaging, and mice with genetic deletion of IGFBP3 to elucidate how synectin promotes fibrosis in vivo. In total, this proposal will utilize conceptually and technically innovative approaches and concepts to test a novel hypothesis pertaining to synectin as a “master regulator” of HSC signals that lead to migration and fibrosis. RELEVANCE (See instructions): Liver injury from alcohol and other etiologies can culminate in cirrhosis with significant associated morbidity and mortality.


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 = $357,750 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	15	4/24/2026	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2025 ( Subtotal = $357,750 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	14	5/15/2025	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2024 ( Subtotal = $357,750 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	13	5/10/2024	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2023 ( Subtotal = $357,750 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	12	5/2/2023	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	Alcohol Research Programs	002	11	9/12/2022	EXTENSION WITH OR WITHOUT FUNDS	$115,680
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	11	4/22/2022	EXTENSION WITH OR WITHOUT FUNDS	$357,750
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	10	9/12/2022	SUPPLEMENT FOR EXPANSION	-$115,680
														Subtotal = $357,750

Issue Date FY: 2021 ( Subtotal = $477,852 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	10	9/7/2021	SUPPLEMENT FOR EXPANSION	$120,102
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	10	4/22/2021	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $477,852

Issue Date FY: 2020 ( Subtotal = $357,750 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	9	4/29/2020	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	Alcohol Research Programs	002	8	8/28/2019	NON-COMPETING CONTINUATION	$0
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	8	4/30/2019	NON-COMPETING CONTINUATION	$357,750
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	8	6/28/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $357,750

Grand Total All Awards = $2,982,102

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Molecular Mechanisms of Liver Fibrosis

Award Number: R37AA021171

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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