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Role of Nicotinamide Nucleotide Adenylyltransferase-1 (NMNAT1) in Chromatin Remodeling and Gene Regulation

Award Number: F31GM146429
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Role of Nicotinamide Nucleotide Adenylyltransferase-1 (NMNAT1) in Chromatin Remodeling and Gene Regulation - PROJECT SUMMARY Chromatin remodeling and gene expression are highly dynamic processes in the nucleus. The regulation of these processes is crucial to maintain proper cellular functions. Chromatin remodeling enzymes mediate changes in chromatin structure and control the cycling of chromatin-associated factors on and off the genome. The remodeling of chromatin depends on metabolites (e.g., ATP and NAD+), which fuels chromatin remodeling enzymes activity. NMNAT1 is a metabolic enzyme primarily involved in the local production of NAD+ in the nucleus. NMNAT1 is thought to provide pools of NAD+ which fuels NAD+-dependent chromatin remodeling enzymes, including SIRT1 and PARP1. However, various studies suggest that NMNAT1 may also allosterically regulate these enzymes activity in an enzymatic independent manner. Nonetheless, the role of NMNAT1 in regulating chromatin remodeling and gene expression through local NAD+ production and interactions with chromatin remodeling enzymes remains poorly defined. In this proposal, I seek to define the role of NMNAT1 in regulating chromatin remodeling enzymes activity, chromatin structure, and gene expression. I hypothesize that the cycling of NMNAT1 on the genome produces local NAD+ gradients that regulate chromatin-modifying enzyme activity, influencing rapid changes in chromatin structure and gene expression of target genes. To address this hypothesis, I will (1) establish an NMNAT1 knock-out cellular system to perform structure-function studies in live cells and identify phenotypical defects upon depletion of NMNAT1. To validate this system, I will perform rescue experiments with wild-type NMNAT1 and catalytic dead mutant NMNAT1. (2) Examine how NMNAT1 regulates the expression of chromatin remodeling enzymes (e.g., SIRT1) target genes by defining changes in chromatin structure, gene expression and genomic occupancy, and (3) establish how NMNAT1 cycling dynamics regulate chromatin remodelers and transcriptional bursting. These studies will be essential to determine how nuclear metabolic enzymes like NMNAT1 and metabolite production regulate chromatin structure and gene expression of target genes. This knowledge will define new paradigms regarding gene expression and regulation. Under the mentorship of Drs. Robert Coleman and Robert H. Singer, Yessenia Cedeno Cedeno will receive multi-disciplinary training in molecular and cellular biology combined with expertise in state-of-the-art microscopy. This will allow Yessenia to successfully execute the proposed research and training plans and advance her professional career as an independent scientist.


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	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	2	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	001	2	6/11/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	2	1/23/2024	NON-COMPETING CONTINUATION	$47,694
														Subtotal = $48,974

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	002	1	3/1/2023	NEW	$942
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	001	1	12/9/2022	NEW	$0
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	1	12/9/2022	NEW	$46,752
														Subtotal = $47,694

Grand Total All Awards = $96,668

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Role of Nicotinamide Nucleotide Adenylyltransferase-1 (NMNAT1) in Chromatin Remodeling and Gene Regulation

Award Number: F31GM146429

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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