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Dietary interventions to modulate heart health in offspring born to diabetic mothers and the subsequent generation.

Award Number: R01HL160980
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Dietary interventions to modulate heart health in offspring born to diabetic mothers and the subsequent generation. - Gestational diabetes and obesity expose the fetus to overnutrition during critical windows of development. Evidence shows that fetal overnutrition increases the risk of heart disease at birth and later in life. What’s more, programmed risk can be passed on to the next generation. The goal of our lab is to develop effective interventions that improve heart health in this readily identifiable population, lessening the burden of heart disease over time. To understand the role of maternal diet in developmentally programmed heart disease, we developed a rat model that compared outcomes of control, diabetes-, high-fat diet-, and combination-exposed offspring. We found that, just like in humans, fetal overnutrition in rats causes cardiac dysfunction at birth and again in adulthood. We also demonstrated that cardiac consequences are due to mitochondrial dysfunction, impaired cardiomyocyte metabolism, and faster cell death following metabolic stress. Importantly, we found that a maternal high-fat diet exaggerates mitochondrial and cardiac dysfunction to increase mortality in offspring born to diabetic mothers (ODM), specifically by increasing fetal overnutrition and programming the cardiac transcriptome to be more susceptible to oxidative damage. While our work highlights the role of maternal dietary fat intake, key questions about programming remain: 1. Does oxidative DNA damage contribute to programmed heart disease in ODM and the next generation? 2. Will limiting fat intake during the last trimester of pregnancy mitigate risks? 3. Can the dietary antioxidant Coenzyme Q (CoQ10) prevent programmed heart disease in ODM and their progeny? Aim 1 will use innovative genomic approaches paired with cardiac phenotyping across generations to establish whether oxidative DNA damage contributes to programmed heart disease following fetal overnutrition. As primary producers of ROS, dysfunctional mitochondria can cause oxidative DNA damage in the form of 8-oxo- 7,8-dihydro-2’-deoxyguanosine (8-oxodG), a mutagenic lesion prone to misrepair and genome instability. Genomic perturbations from 8-oxodG have been linked to metabolic disease, early ageing, and inflammation; moreover, they may be inheritable. We will determine whether 8-oxodG contributes to programmed heart disease in our model by comparing whole genome levels and downstream genomic perturbations using oxiDIP-seq. We will also use scRNA-sequencing of blastocysts from F0 females and their F1 and F2 offspring to delineate the timing of newly acquired mutations and whether there is compounding or dilution from DNA repair mechanisms across generations. Aims 2 and 3 will determine whether dietary interventions including limiting dietary fat intake in the last third of pregnancy or supplementing high-risk females with dietary CoQ10 during ovulation and fertilization will decrease the risk of developmentally programmed heart disease in ODM and their progeny. Findings are needed to understand mechanisms, inheritance patterns, and the effects of clinically applicable interventions such as expanding diabetic screening and dietary counseling to include management of maternal hyperlipidemia as well as hyperglycemia or offering preventative dietary supplementation during family planning.


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 = $415,000 )
2026	2026	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	000	5	2/26/2026	NON-COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2025 ( Subtotal = $415,000 )
2025	2025	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	000	4	1/16/2025	NON-COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2024 ( Subtotal = $415,000 )
2024	2024	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	000	3	12/30/2023	NON-COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2023 ( Subtotal = $415,000 )
2023	2023	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cardiovascular Diseases Research	001	2	3/10/2023	NON-COMPETING CONTINUATION	$41,500
2023	2023	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cardiovascular Diseases Research	000	2	1/11/2023	NON-COMPETING CONTINUATION	$373,500
														Subtotal = $415,000

Issue Date FY: 2022 ( Subtotal = $415,000 )
2022	2022	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cardiovascular Diseases Research	000	1	1/10/2022	NEW	$415,000
														Subtotal = $415,000

Grand Total All Awards = $2,075,000

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Dietary interventions to modulate heart health in offspring born to diabetic mothers and the subsequent generation.

Award Number: R01HL160980

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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