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Hepatic mTORC1 Signaling and the Regulation of Lipid Homeostasis

Award Number: R01DK125497
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Hepatic mTORC1 Signaling and the Regulation of Lipid Homeostasis - Disorders associated with altered lipid metabolism such as non-alcoholic fatty liver disease (NAFLD) and atherosclerosis are a significant health threat to the U.S. population. As result, it is imperative to define the molecular mechanisms driving abnormal lipid homeostasis to identify new and effective therapeutics. Insulin- resistance is one of the most significant risk factors for lipid dysfunction; however, significant knowledge gaps remain in our understanding of how abnormal insulin action leads to altered lipid metabolism in metabolic disease. The liver is responsible for regulating the rates of lipid production and breakdown to control systemic lipid homeostasis. Dysregulation of these processes underly the pathogenesis of dyslipidemia and NAFLD, the latter consisting of a spectrum of liver diseases that encompasses simple liver steatosis (NAFL) and non- alcoholic steatohepatitis (NASH). Work by several laboratories including ours have implicated liver insulin signaling via the AKT-mTORC1 pathway in the regulation of lipid metabolism. Recent work from our laboratory uncovered a novel function for liver mTORC1 signaling in the regulation of phospholipid metabolism that is essential for the proper control of both hepatic and systemic lipid levels by insulin. This discovery has important implications to NAFLD and dyslipidemia and adds significant mechanistic insight into the role of insulin signaling via mTORC1 in the regulation of lipid metabolism. In Aim 1 of this proposal, we will build on these important observations and define the molecular mechanism underlying mTORC1's control of phosphatidylcholine biosynthesis and hepatic lipid homeostasis. In Aim 2, we will explore the therapeutic potential of manipulating liver mTORC1 signaling in the initiation and progression of NAFLD using multiple models of NASH. Collectively, this proposal will build upon recent discoveries regarding the role of insulin signaling via mTORC1 in the regulation of hepatic lipid metabolism. These experiments have the potential to significantly affect our mechanistic understand of the metabolic pathways that connect abnormal insulin signaling to NAFLD and dyslipidemia, which will provide the foundation for new therapeutic targets for fatty liver disease and pro- atherogenic dyslipidemia.


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 = $0 )
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $409,950 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/22/2024	NON-COMPETING CONTINUATION	$384,328
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/13/2024	NON-COMPETING CONTINUATION	$25,622
														Subtotal = $409,950

Issue Date FY: 2023 ( Subtotal = $427,654 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/30/2023	NON-COMPETING CONTINUATION	$427,654
														Subtotal = $427,654

Issue Date FY: 2022 ( Subtotal = $428,417 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/19/2022	NON-COMPETING CONTINUATION	$385,575
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/29/2022	NON-COMPETING CONTINUATION	$42,842
														Subtotal = $428,417

Issue Date FY: 2021 ( Subtotal = $427,991 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/17/2021	NEW	$0
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/15/2021	NEW	$427,991
														Subtotal = $427,991

Grand Total All Awards = $1,694,012

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Hepatic mTORC1 Signaling and the Regulation of Lipid Homeostasis

Award Number: R01DK125497

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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