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Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation

Award Number: R01GM138393
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation - Project Summary Environmental nutrient availability and metabolism profoundly affects an individual’s health, while deregulation of nutrient signaling contributes to many diseases, including cancer. Nutrient signaling and metabolism regulate the epigenome to affect cellular phenotype and function, yet mechanisms explaining how nutrients signal to the epigenome are lacking. Defining these mechanisms constitutes a critical scientific problem that is essential to address. By defining these mechanisms, we will understand how nutrient exposures affect health, and how aberrant nutrient signaling causes disease. The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved nutrient activated signaling pathway. MTORC1 responds to diverse nutrient and metabolic inputs to promote cell growth and proliferation, and it is deregulated in cancer and other diseases. While mTORC1 is an emerging epigenetic regulator, how it signals to the epigenome is unknown. In this project, we will use a yeast model to build on our previous successes to define these mechanisms. Herein, we will test the overarching hypothesis that TORC1 signaling controls the chromatin binding of architectural proteins and histone reader proteins that maintain viability during nutrient stress and regulate metabolic gene expression. In Aim I, we will identify specific epigenetic pathways acting on histone H3 that promote binding of high mobility group box (HMGB) proteins to chromatin to prevent cell death under nutrient stress conditions. We then will define biochemically and genetically how non-chromatin bound HMGB proteins cause cell death during TORC1 stress. Stressed human cells evict HMGB1 from chromatin to affect cytoplasmic metabolic activities, initiate innate immune signaling and inflammation, and promote tumorigenesis. These yeast studies will identify conserved epigenetic pathways that are critical for retaining HMGB1 on chromatin during mTORC1 stress to prevent such HMGB1-induced pathological effects. Aim II will use proteomic and genomic approaches to define how yeast TORC1 represses conserved sirtuin histone deacetylase activity to regulate histone reader chromatin binding and control mitochondrial metabolic transcription. We then will perform mechanistic studies to assess how these histone reader proteins transcriptionally regulate metabolic gene expression. By the project’s conclusion, we will have defined novel and conserved mechanisms used by TORC1 to modify the epigenome, which prevent cell death during nutrient stress and regulate metabolic gene transcription. These mechanisms will be directly relevant for understanding how human mTORC1 deregulation alters the epigenome to cause disease.


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 = $308,000 )
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Biomedical Research and Research Training	000	4	6/23/2025	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2024 ( Subtotal = $308,000 )
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Biomedical Research and Research Training	000	3	6/13/2024	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2023 ( Subtotal = $308,000 )
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Biomedical Research and Research Training	000	2	6/23/2023	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2022 ( Subtotal = $308,000 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Biomedical Research and Research Training	000	1	6/24/2022	NEW	$308,000
														Subtotal = $308,000

Grand Total All Awards = $1,232,000

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Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation

Award Number: R01GM138393

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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