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In utero rescue of cleft palate using maternal administration of folic acid

Award Number: R21DE032742
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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In utero rescue of cleft palate using maternal administration of folic acid - PROJECT SUMMARY Craniofacial anomalies accompany a third of all birth defects, with isolated or nonsyndromic clefts of the lip and palate (CL/P) alone occurring in 1/700 births worldwide. These isolated CL/P have a complex etiology including both genetic and environmental factors. Isolated cleft palate (CP) alone accounts for 1/1700 cases in the US. In addition, there are >400 syndromes with CP as a phenotype. Environmental factors such as folate intake and smoking have been shown to affect maternal environment. While dietary maternal folic acid supplementation has consistently shown ameliorative effects on neural tube defects, its effect on reducing the occurrence of CL/P has been variable both in human and in mouse models. Sources of this variability include the dosage and delivery of folic acid as well as ability to assess the impact of the treatment in mouse models. Several human studies have speculated that low folic acid dose is not sufficient to prevent CL/P, and that higher doses are more effective. Our preliminary data indicate that a high daily dose of folic acid given intraperitoneally to pregnant mice in two short developmental windows is sufficient to rescue CP in utero in Specc1l mouse model of CP. Specc1l deficiency leads to actin cytoskeletal defects, which results in palatal shelf elevation delay. We have developed several quantitative 2-D and 3-D analyses to characterize the timing and cellular changes that occur during palatal shelf growth and elevation. We posit that in utero folic acid supplementation has an ameliorative effect on the dynamics of palate closure. In contrast to neural tube defects, we argue that rescue of CP requires a higher daily dose of folic acid administered intraperitoneally but for a short window of time. To our knowledge, we are the first to use intraperitoneal injection of folic acid to rescue CP. Folic acid has been used extensively in human studies and has been safe even at relatively high doses. The objective of this proposal is to determine the minimum possible dose and treatment window for an effective rescue of CP and to study which aspects of palate closure dynamics are impacted by folic acid supplementation. We will also use sophisticated proteomic and phosphoproteomic analysis of palatal shelf tissue to determine the molecular consequence of folic acid treatment. Together, these studies will establish the experimental system and methods to study maternal folic acid rescue of CP in mice that can be applied to other mouse models. Importantly, these studies will lead to future therapeutic strategies to reduce the incidence of CL/P in humans.


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: 2024 ( Subtotal = $193,750 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Oral Diseases and Disorders Research	001	2	6/18/2024	NON-COMPETING CONTINUATION	$19,375
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Oral Diseases and Disorders Research	000	2	1/25/2024	NON-COMPETING CONTINUATION	$174,375
														Subtotal = $193,750

Issue Date FY: 2023 ( Subtotal = $232,500 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Oral Diseases and Disorders Research	000	1	2/24/2023	NEW	$232,500
														Subtotal = $232,500

Grand Total All Awards = $426,250

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In utero rescue of cleft palate using maternal administration of folic acid

Award Number: R21DE032742

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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