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Molecular sensors for metabolic programming of the sperm epigenome and offspring physiology

Award Number: R01HD103027
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Molecular sensors for metabolic programming of the sperm epigenome and offspring physiology - Project Summary / Abstract Recent research has established that epigenetic information inherited from the father has an impact on the physiology of his children, and that this information varies depending on environmental exposure and metabolic status of the father. There is also now a substantial body of evidence that paternally inherited epigenetic information may contribute to childhood obesity and other significant public health problems, depending on paternal diet. Mechanistic insights are still scarce, however, and it remains unclear which dietary factors may be able to modify epigenetic programming of sperm in a way that affects metabolism in the offspring. Addressing this important problem, this project will test the central hypothesis that reduced paternal metabolic nicotinamide adenine dinucleotide (NAD+) levels result in heritable sperm-borne epimodifications that modulate offspring metabolism. NAD+ is a central molecule involved in energy metabolism and it also serves as a substrate of epigenetic regulators such as sirtuins, including histone deacetylases, and poly(ADP- ribose) polymerases involved in sperm epigenetic programming and the regulation of energy metabolism. Vitamin B3 (niacin, nicotinamide) is the main dietary precursor of NAD+ synthesis in humans. This project proposes to utilize an innovative transgenic mouse model of acquired niacin deficiency (ANDY) that permits for the first time to study effects of low NAD+ levels, as seen in parts of the human population, in a laboratory animal. Our preliminary data show that suboptimal levels of NAD+ in ANDY males resulted in progeny with smaller body size, altered insulin sensitivity, and altered carbohydrate and lipid metabolism, which indicates that the micronutrient niacin may be of previously unrecognized importance for epigenetic programming of sperm. The objectives of the proposed work are (1) to characterize the metabolism of NAD+-deficient males and their F1 progeny, where we expect to identify heritable adaptations of energy metabolism that depend on paternal nutritional status, (2) to test the hypothesis that low NAD+ levels in males result in elevated sperm histone acetylation and differential sperm histone positioning, which are expected to include metabolic genes whose regulation is affected in F1 progeny, and (3) to determine the nature and extent of altered gene expression profiles in F1 progeny. We further propose to determine the extent to which pharmacological intervention, e.g. supplementation therapy, can prevent such changes. We expect that DNA methylation levels will be altered in gene loci in offspring as a consequence of abnormal sperm histone acetylation in NAD+-deficient sires. In summary, the proposed studies are expected to establish NAD+ as a molecular link between paternal nutrition and metabolic state, sperm chromatin-mediated epigenetic inheritance, and the regulation of offspring metabolism, including metabolic disease. The expected results should be relevant for the future development of avoidance and periconceptional nutritional supplementation strategies for men with the goal to maximize chances that children are born healthy.


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: 2026 ( Subtotal = $0 )
2026	2025	UTAH STATE UNIVERSITY	1000 OLD MAIN HL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	5	2/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $307,934 )
2025	2025	UTAH STATE UNIVERSITY	1000 OLD MAIN HL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	5	4/3/2025	NON-COMPETING CONTINUATION	$307,934
														Subtotal = $307,934

Issue Date FY: 2024 ( Subtotal = $305,136 )
2024	2024	UTAH STATE UNIVERSITY	1000 OLD MAIN HL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	001	4	5/2/2024	NON-COMPETING CONTINUATION	$27,740
2024	2024	UTAH STATE UNIVERSITY	1000 OLD MAIN HL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	4	3/20/2024	NON-COMPETING CONTINUATION	$277,396
														Subtotal = $305,136

Issue Date FY: 2023 ( Subtotal = $308,489 )
2023	2023	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	3	3/27/2023	NON-COMPETING CONTINUATION	$308,489
														Subtotal = $308,489

Issue Date FY: 2022 ( Subtotal = $308,746 )
2022	2022	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	2	4/27/2022	NON-COMPETING CONTINUATION	$308,746
														Subtotal = $308,746

Issue Date FY: 2021 ( Subtotal = $311,420 )
2021	2021	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	1	4/5/2021	NEW	$311,420
														Subtotal = $311,420

Grand Total All Awards = $1,541,725

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Molecular sensors for metabolic programming of the sperm epigenome and offspring physiology

Award Number: R01HD103027

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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