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Cardiovascular disease in fetal alcohol spectrum disorder

Award Number: U01AA030185
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Cardiovascular disease in fetal alcohol spectrum disorder - Project Summary The incidence of congenital heart defects (CHDs) and cardiovascular disease (CVD) in patients with fetal alcohol spectrum disorder (FASD) are poorly characterized. Cardiovascular abnormalities may be common in FASD; however, comprehensive retrospective studies on lifetime CVD risk in adult patient cohorts have yet to be performed. Cellular and molecular mechanisms underlying FASD-mediated CHD and CVD are also largely unknown along with any biomarkers that would allow the patient population to be stratified based on CVD risk. Here we present preliminary data from our retrospective clinic cohort that demonstrate that females with FASD have an overall increase in CHD, myocardial infarction (MI) rate, and the likelihood of being diagnosed with any CVD in adulthood. Females with FASD also have significantly reduced ejection fraction relative to matched controls. These data suggest that FASD is a risk factor for CHD in newborns and CVD in adults. In a zebrafish model of embryonic alcohol exposure (EAE), we confirmed a primary defect in cardiomyocyte migration that causes subsequent functional and structural heart abnormalities, including contractility deficits and ventricular wall abnormalities that persist through adulthood. Our findings indicate that EAE zebrafish can serve as a model for lifelong cardiac function in the presence and absence of CHD. We propose three Specific Aims to test the central hypothesis that FASD patients have an increased incidence of CVD and that the zebrafish EAE model will uncover novel molecular mediators and biomarkers that explain and predict CVD risk. In Specific Aim 1, we will perform a retrospective study to determine CVD incidence in an adult FASD patient cohort, including CHD, hypertension, cardiomyopathy, MI, cerebrovascular accident, and embolism, as well as their association with other metabolic and inflammatory conditions. In Specific Aim 2, we will define molecular mechanisms underlying embryonic heart defects in a zebrafish EAE model by identifying and functionally evaluating the impact of molecular alterations in migratory myl7+ cardiomyocytes that form the cardiac cone through hypothesis-driven (PDGF pathway) and unbiased (bulk RNA-sequencing on FACS-isolated myl7+ cardiomyocytes) approaches. In Specific Aim 3, we will test the hypothesis that EAE adults with a CHD are susceptible to cardiac dysfunction and cardiomyopathy due to lasting alterations in cardiac structure, function, and molecular signature. Taken together, the proposed studies will provide fundamental insights into the cardiovascular health outcomes of patients with FASD, reveal novel molecular mediators of EtOH-induced CHDs, and identify biomarkers of adult cardiac dysfunction in EAE adults. Cardiovascular diseases may contribute significantly to morbidity and mortality in affected patients. By identifying which CVD outcomes impact FASD patients and what additional metabolic and inflammatory factors indicate risk, we will provide an opportunity for early intervention. Further, identification of molecular mediators of CHD and cardiomyopathy in a zebrafish model of EAE will allow us to expand our mechanistic understanding of the effects of PAE across the lifespan.


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 = $343,380 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Alcohol Research Programs	000	4	6/3/2025	NON-COMPETING CONTINUATION	$343,380
														Subtotal = $343,380

Issue Date FY: 2024 ( Subtotal = $343,380 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Alcohol Research Programs	001	3	5/9/2024	NON-COMPETING CONTINUATION	$343,380
2024	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Alcohol Research Programs	000	2	1/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,380

Issue Date FY: 2023 ( Subtotal = $343,380 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Alcohol Research Programs	000	2	5/4/2023	NON-COMPETING CONTINUATION	$343,380
														Subtotal = $343,380

Issue Date FY: 2022 ( Subtotal = $343,380 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Alcohol Research Programs	000	1	8/9/2022	NEW	$343,380
														Subtotal = $343,380

Grand Total All Awards = $1,373,520

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Cardiovascular disease in fetal alcohol spectrum disorder

Award Number: U01AA030185

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/10/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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