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Gene x Environment Interactions and Congenital Heart Defects – Illuminating the Mechanisms

Award Number: R01HD113214
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Gene x Environment Interactions and Congenital Heart Defects – Illuminating the Mechanisms - PROJECT SUMMARY The causes of most non-syndromic structural birth defects remain unknown due to their complex causes where genetic and environmental factors (GxE) interact to cause disease. Understanding how GxE converges to alter embryonic development is critical for devising preventive strategies to reduce risks. Recent work by the Zohn laboratory established a new mouse model to study the mechanisms underlying GxE interactions and congenital heart defects (CHDs). Extensive preliminary studies with this mouse model led us to formulate our central hypotheses: GxE converges to alter gene expression in cardiac progenitor cells to alter cell fate, and different genetic variants in critical genes can have divergent effects on GxE interactions. We propose two Specific Aims that use our GxE mouse models to illuminate how GxE interacts to cause CHDs. Our experimental design involves altering the vitamin A content of the maternal diet (Environmental factor) in mice carrying a mutation in Hectd1 (Genetic factor), a novel ubiquitin ligase discovered in the Zohn laboratory. We show that while neither heterozygous mutation of Hectd1 nor mild vitamin A deficiency results in CHDs, the combination of the two causes CHDs. Mechanistically we demonstrate that Hectd1 is required for vitamin A/retinoic acid signaling, yet how HECTD1 regulates signaling remains unknown. The aims of this project are 1) to determine how GxE converges to cause CHDs in our model and 2) to elucidate how HECTD1 regulates retinoic acid signaling utilizing an allelic series of truncated HECTD1 mouse lines that model human CHD-associated mutations. Interestingly, our preliminary studies indicate that distinct mutations in HECTD1 disrupt retinoic acid signaling differently. Successful completion of these aims will: 1) provide a deeper mechanistic understanding of how GXE interacts to cause CHDs by elucidating which critical developmental processes are disrupted in our GxE model; 3) reveal how HECTD1 regulates RA signaling; and 4) link our animal studies to human disorders by modeling patient mutations in mouse models and determining how these mutations differentially interact with maternal vitamin A intake. These studies will reveal the mechanisms of how GxE interaction alters the development of the heart and pinpoint critical targets for preventing birth defects.


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 = $553,451 )
2025	2025	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	3	4/9/2025	NON-COMPETING CONTINUATION	$553,451
														Subtotal = $553,451

Issue Date FY: 2024 ( Subtotal = $638,305 )
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	2	5/1/2024	NON-COMPETING CONTINUATION	$638,305
														Subtotal = $638,305

Issue Date FY: 2023 ( Subtotal = $600,009 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	1	7/20/2023	NEW	$600,009
														Subtotal = $600,009

Grand Total All Awards = $1,791,765

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Gene x Environment Interactions and Congenital Heart Defects – Illuminating the Mechanisms

Award Number: R01HD113214

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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