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Elucidating the role of hepatic mTORC2 as a key regulator of carbohydrate metabolism in non-alcoholic fatty liver disease

Award Number: F31DK129018
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 05/24/2024

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Elucidating the role of hepatic mTORC2 as a key regulator of carbohydrate metabolism in non-alcoholic fatty liver disease - Project Summary Non-alcoholic fatty liver disease (NAFLD) currently effects around 30% of Americans and costs the U.S approximately $103 billion annually. However, the standard of care remains lifestyle changes and liver transplantation with currently no FDA approved therapies. NAFLD often correlates with obesity which is rising in both developed and developing nations. Mammalian target of rapamycin complex 2 (mTORC2) is emerging as a central hub for carbohydrate and lipid metabolism, with its activation having been linked to NAFLD in mice. These recent studies have highlighted a role for mTORC2 modulation during high-fat diets in mice, where hepatic mTORC2 ablation provides a protective effect against high-fat induced hepatic steatosis. However, the dietary supplements that have been most attributed to the rise of NAFLD in humans are carbohydrates, specifically fructose. While protective effects of mTORC2 ablation in the liver during high-fat diet have been investigated, its impact on high-carbohydrate diets has been neglected. Here, I will examine the ability for mTORC2 to protect against high-carbohydrate induced hepatic steatosis, as has previously been seen in the context of high-fat diets. Mechanistically, I will investigate the role by which hepatic mTORC2 regulates carbohydrate derived acetyl-CoA synthesis and utilization, subsequently promoting the pathogenesis of NAFLD. I will accomplish this by examining two distinct acetyl-CoA producing enzymes: ACLY and ACSS2. Not only will I investigate mTORC2’s role in regulating both ACLY and ACSS2 through phosphorylation, but also for the first time, investigate mTORC2 loss in an acute setting using an auxin degron system, which is a plant based endogenous degradation tag. With the completion of this proposed work, I strongly believe that a more detailed and mechanistic understanding of hepatic signaling, and metabolism will be obtained, providing targets which could ultimately be used to treat NAFLD and other metabolic diseases.


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 = -$30,292 )
2025	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/23/2024	NON-COMPETING CONTINUATION	-$19,309
2025	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/25/2025	NON-COMPETING CONTINUATION	-$10,983
														Subtotal = -$30,292

Issue Date FY: 2024 ( Subtotal = $36,180 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/7/2023	NON-COMPETING CONTINUATION	$34,900
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/22/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $36,180

Issue Date FY: 2023 ( Subtotal = $34,900 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/8/2022	NON-COMPETING CONTINUATION	$33,958
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/17/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $34,900

Issue Date FY: 2022 ( Subtotal = $33,958 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/16/2021	NEW	$33,242
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	12/16/2021	NEW	$0
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	4/29/2022	NEW	$717
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	5/26/2022	NEW	-$1
														Subtotal = $33,958

Grand Total All Awards = $74,746

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Elucidating the role of hepatic mTORC2 as a key regulator of carbohydrate metabolism in non-alcoholic fatty liver disease

Award Number: F31DK129018

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 05/24/2024

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