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Acute Prenatal Alcohol Exposure Potentiates Conotruncal Defects in the Setting of a Permissive Genetic Background

Award Number: F30AA029936
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/18/2022
PERIOD OF PERFORMANCE END DATE: 05/17/2027

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Acute Prenatal Alcohol Exposure Potentiates Conotruncal Defects in the Setting of a Permissive Genetic Background - PROJECT SUMMARY/ABSTRACT Nearly 30% of patients with Fetal Alcohol Spectrum Disorder (FASD) have a congenital heart defect (CHD). Outflow tract (OFT) defects are over-represented, though with variable incidence and severity. The majority of prenatal alcohol exposure (PAE) research focuses on the hallmarks of FASD, chronic drinking and neurologic defects. The most common form of PAE in the population, acute exposure during the periconceptual period, and its effect on cardiac development have not been studied. We will study the effects of acute, periconceptual drinking both through a multi-institutional clinical study and with our acute PAE murine model, in which mice receive two intraperitoneal injections of 3g/kg of 30% ethanol at a point critical to cardiac organogenesis. We hypothesize the variable incidence and severity of PAE-induced OFT defects can be explained by a combination of PAE and otherwise non-deleterious mutations that result in a genetically permissive background. We believe mutations in the Notch pathway establish such a genetically permissive background, and that PAE acts synergistically with these mutations via epigenetic regulation of Notch to result in OFT malformation. Aim 1 of this study will address the specificity of the deleterious effects of PAE to OFT alignment and define the molecular pathways disrupted in individuals with PAE-induced OFT defects. We will achieve this through relative risk analysis of PAE and CHD diagnoses and pathway and subsequent logistical regression analyses of whole genome sequencing data. Aim 2 will define alcohol driven epigenetic regulation as the mechanism by which acute PAE and otherwise non-deleterious Notch pathway mutations synergistically disrupt OFT development. Using a combination of molecular assays and histologic analysis in vitro and in vivo, we will test the impact of this combined teratogenic insult on second heart field (SHF) viability and ability to migrate into the OFT. We will establish PAE driven epigenetic regulation, disrupting Notch gene accessibility and transcription, inhibits Notch signaling and use a pan-histone acetyltransferase inhibitor in vitro to demonstrate prevention of PAE induced hyperacetylation is sufficient to rescue Notch signaling and SHF viability. Similarly, rescue of SHF viability by overexpression of notch intracellular domain (NICD) in vitro will cement the point of acute PAE and Notch mutation synergy as loss of Notch signaling prohibiting SHF viability. As one of the first studies to examine the interaction of clinically relevant acute PAE with heart development, this study addresses the priorities of the NIAAA to define the impact of non-chronic exposure and alcohol’s effects on understudied organ systems. The genetic pathways identified by this study, including novel validation of the Notch pathway as significant in PAE-induced CHD, will provide targets for disease prevention and identification of those most at risk to develop the world’s most common and deadly birth defect. Completion of this project is ensured by the technical training and mentorship by the sponsorship team, the training site’s cutting-edge facilities, and education provided by the principal investigator’s M.D.-Ph.D. program.


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 = $54,538 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Alcohol Research Programs	001	4	6/5/2025	NON-COMPETING CONTINUATION	$564
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Alcohol Research Programs	000	4	5/7/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Alcohol Research Programs	000	3	5/2/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Alcohol Research Programs	000	2	4/14/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,753 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Alcohol Research Programs	000	1	5/18/2022	NEW	$51,753
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Alcohol Research Programs	001	1	5/18/2022	NEW	$0
														Subtotal = $51,753

Grand Total All Awards = $212,959

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Acute Prenatal Alcohol Exposure Potentiates Conotruncal Defects in the Setting of a Permissive Genetic Background

Award Number: F30AA029936

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/18/2022

PERIOD OF PERFORMANCE END DATE: 05/17/2027

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