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Impact of maternal dietary vitamin A on risk and severity of cleft lip/palate in genetically sensitized embryos

Award Number: R01HD113989
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: 08/02/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Impact of maternal dietary vitamin A on risk and severity of cleft lip/palate in genetically sensitized embryos - Project Summary The term “Cleft lip with or without cleft palate (CL/P)” encompasses a variety of clinical presentations that collectively represent one of the most common human birth defects. For each patient, the impact can also be significant. The severity of a patient’s clinical presentation is the major determinant of the duration and frequency of significant surgical intervention and long-term clinical care. Considerable progress has been made over the last few decades to determine the genes responsible for syndromic forms of CL/P. However, the low penetrance and variability in presentation pose challenges when counseling families about recurrence risks, as it is currently impossible to predict whether a child will be born with CL/P or how severe the presentation might be regardless of whether a genetic predisposition is known. This new proposal builds on important new observations and exciting preliminary data on established mouse models of CL/P to begin to dissect the factors that influence the cleft penetrance and severity in embryos that are genetically predisposed to CL/P. Specifically, this project will address the role of maternal diet (specifically vitamin A) as a modifier of genetic susceptibility, severity of presentation and in utero correction prior to birth, as well as investigate the basis for the left bias in unilateral cleft presentations. Although vitamin A and its derivatives have long been implicated as a risk factor in CL/P, this project will exploit a novel mouse mutant background that overcomes the limitations of prior animal model studies such as the need for excessive, non-physiologic levels of vitamin A and unnatural routes of administration. Furthermore, we test the impact on two distinct underlying genetic susceptibilities. The successful demonstration of modifying roles for these factors could ultimately have a significant impact on patient counselling and potentially open up the possibility of developing simple and effective interventional and preventative maternal dietary interventions such as personalized dietary supplementation for mothers carrying CL/P risk alleles, or crop biofortification approaches for whole populations where dietary deficiencies and genetic risk factors are known. Such approaches could have a profound impact on the incidence of NS-CL/P, much like the successes seen for maternal folic acid supplementation for reducing the risk of neural tube 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: 2026 ( Subtotal = $336,475 )
2026	2026	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	3	4/28/2026	NON-COMPETING CONTINUATION	$336,475
														Subtotal = $336,475

Issue Date FY: 2025 ( Subtotal = $336,475 )
2025	2025	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	2	4/14/2025	NON-COMPETING CONTINUATION	$336,475
														Subtotal = $336,475

Issue Date FY: 2024 ( Subtotal = $336,475 )
2024	2024	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Child Health and Human Development Extramural Research	000	1	8/2/2024	NEW	$336,475
														Subtotal = $336,475

Grand Total All Awards = $1,009,425

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Impact of maternal dietary vitamin A on risk and severity of cleft lip/palate in genetically sensitized embryos

Award Number: R01HD113989

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: 08/02/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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