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Role of Beta Spectrin and Smad in Alcohol-Induced Liver and GI Cell Proliferation

Award Number: R01AA023146
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: 08/20/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Role of Beta Spectrin and Smad in Alcohol-Induced Liver and GI Cell Proliferation - PROJECT SUMMARY Alcohol-related liver disease (ALD) and nonalcoholic steatohepatitis (NASH) are two reasons Americans mostly require a liver transplant. Furthermore, aldehyde dehydrogenase gene 2 (ALDH2) deficiency, which impairs alcohol and lipid metabolism, affects ~560 million people globally. Our earlier studies show that a pathway from TGF-β to βII-spectrin (encodes the disordered protein βII-spectrin) via SMAD3 (a TGF-β -activated transcription factor) is essential for proper development of the liver and preventing many liver pathologies. βII-spectrin-deficient mice are highly susceptible to alcohol-induced liver injury, and complete knockout of this gene results in embryonic death with features like fetal alcohol syndrome. Compromised TGF-β signaling through SMAD3 and βII-spectrin dysregulates ALDH1A and ALDH2 genes and disrupts DNA repair, contributing to oncogenesis from elongated telomeres and genome instability. To explore the roles of βII-spectrin and the TGF-β pathway in aldehyde-related and alcohol-related liver injury, we generated Aldh2-/-Sptbn1+/- (ASKO) double-knockout mice, which become obese and develop NASH and characteristics of metabolic syndrome (MetS). Their livers have altered lipid profiles, increased reactive aldehydes, and increased lipid synthesis. Treating Aldh2-/- mice with siRNA targeting βII-spectrin reduces diet- induced lipid accumulation and improves glucose handling. We hypothesize that hepatocyte stress from high lipid levels, reactive aldehydes, such as 4-hydroxynonenol (4-HNE), or inflammation activates caspases that cleave βII-spectrin, which, in turn, promote lipid synthesis by interacting with SREBP1 (sterol regulatory element binding protein1). This process also diverts βII-spectrin from TGF-β-SMAD3 signaling, activating fibrogenic and oncogenic pathways instead. We will explore how cleavage of βII-spectrin and aldehyde-modification of βII- spectrin affect the interactions between βII-spectrin, SMAD3, and SREBP1 by addressing the following specific aims: Aim 1. Determine the hepatocyte-specific roles of βII-spectrin by studying Aldh2-/- mice crossed with liver-specific Sptbn1 knockout mice. Aim 2. Define molecular mechanisms by which the interaction between βII-spectrin and SREBP1 promotes lipogenesis. Aim 3. Assess the translational relevance of SPTBN1 and ALDH2 in human obesity and NASH, and if pathological effects are reduced by siRNA targeting βII-spectrin. The outlined studies are aimed at improving the understanding of diet-induced fatty liver disease in the context of ALDH2 deficiency. The outcomes promise to expose the many intricacies of liver diseases and inform the development of novel intervention strategies for liver-associated diseases, such as MetS, ALD, NAFLD, and NASH.


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 = $443,383 )
2025	2025	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	19	7/29/2025	NON-COMPETING CONTINUATION	$443,383
														Subtotal = $443,383

Issue Date FY: 2024 ( Subtotal = $443,383 )
2024	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	001	18	8/20/2024	COMPETING CONTINUATION	$443,383
2024	2022	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	17	8/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $443,383

Issue Date FY: 2022 ( Subtotal = $376,875 )
2022	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	17	3/31/2022	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2021 ( Subtotal = $376,875 )
2021	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	004	16	9/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$76,398
2021	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	001	16	7/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,875
2021	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	003	15	9/10/2021	NON-COMPETING CONTINUATION	-$76,398
2021	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	002	15	7/26/2021	NON-COMPETING CONTINUATION	$0
2021	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	15	7/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,875

Issue Date FY: 2020 ( Subtotal = $358,875 )
2020	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	15	3/20/2020	NON-COMPETING CONTINUATION	$358,875
														Subtotal = $358,875

Issue Date FY: 2019 ( Subtotal = $358,875 )
2019	2019	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	002	14	3/21/2019	NON-COMPETING CONTINUATION	$358,875
2019	2018	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	001	13	10/29/2018	COMPETING CONTINUATION	$85
2019	2017	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	12	10/29/2018	NON-COMPETING CONTINUATION	-$85
														Subtotal = $358,875

Issue Date FY: 2018 ( Subtotal = $358,875 )
2018	2018	THE GEORGE WASHINGTON UNIVERSITY	2121 I ST NW STE 601	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	13	6/13/2018	COMPETING CONTINUATION	$358,875
														Subtotal = $358,875

Issue Date FY: 2017 ( Subtotal = $285,300 )
2017	2017	THE GEORGE WASHINGTON UNIVERSITY	2121 I ST NW STE 601	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	12	7/3/2017	NON-COMPETING CONTINUATION	$285,300
														Subtotal = $285,300

Issue Date FY: 2016 ( Subtotal = $285,300 )
2016	2016	GEORGE WASHINGTON UNIVERSITY	44983 KNOLL SQUARE	ASHBURN	VA	20147	LOUDOUN	USA	Alcohol Research Programs	002	11	6/9/2016	NON-COMPETING CONTINUATION	$285,300
2016	2015	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Alcohol Research Programs	000	9	12/14/2015	NON-COMPETING CONTINUATION	-$275,796
2016	2015	GEORGE WASHINGTON UNIVERSITY	44983 KNOLL SQUARE	ASHBURN	VA	20147	LOUDOUN	USA	Alcohol Research Programs	001	10	12/14/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$275,796
														Subtotal = $285,300

Issue Date FY: 2015 ( Subtotal = $279,360 )
2015	2015	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Alcohol Research Programs	000	9	6/24/2015	NON-COMPETING CONTINUATION	$279,360
														Subtotal = $279,360

Issue Date FY: 2014 ( Subtotal = $279,360 )
2014	2014	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Alcohol Research Programs	000	8	7/1/2014	NON-COMPETING CONTINUATION	$279,360
														Subtotal = $279,360

Issue Date FY: 2013 ( Subtotal = $288,000 )
2013	2013	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Alcohol Research Programs	000	7	9/19/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$288,000
														Subtotal = $288,000

Grand Total All Awards = $4,134,461

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Role of Beta Spectrin and Smad in Alcohol-Induced Liver and GI Cell Proliferation

Award Number: R01AA023146

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: 08/20/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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