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Role of SPECC1L cytoskeletal protein in palate elevation dynamics

Award Number: R01DE032825
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: 08/10/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Role of SPECC1L cytoskeletal protein in palate elevation dynamics - PROJECT SUMMARY Orofacial clefts involving the lip and palate are the most common congenital craniofacial malformation that occur as part of >400 syndromes or as an isolated phenotype in ~1/700 live-births. Non-syndromic cleft palate only by itself afflicts 1/1700 children with a 2:1 increased incidence in females. The lifetime cost for medical treatment, educational services, and lost productivity averages more than $100,000 per affected person. Embryonic palatogenesis involves bilateral vertical outgrowth of shelves from the maxilla that elevate horizontally and fuse above the tongue. While palatogenesis has been studied for more than a century, it is not clear how palatal shelves reorient from the vertical to horizontal direction during elevation. One reason for this knowledge gap is that this process is rapid and therefore hard to time and capture. Another is a lack of methodologies to assess palate elevation and of mouse models with a well-characterized palate elevation delay. Our studies show that palatal shelves elevate in less than 3 hours in utero and that there is a defined embryonic window of time for elevation. We have also assessed the dynamic interplay of cell proliferation, cell orientation and actomyosin contraction that underlies normal palatal shelf elevation. We have established novel methodologies to use MRI for in utero imaging and to use finite element analysis to model palatal shelf elevation. In addition, we have been studying the role of cytoskeletal scaffolding protein SPECC1L in palatogenesis. We identified the first de novo autosomal dominant SPECC1L mutations in patients with orofacial clefts. We and others have now shown that patients with SPECC1L mutations clustered in the second coil ed coil domain (CCD2) or calponin homology domain (CHD) commonly manifest hypertelorism, cleft palate and omphalocele among other phenotypes. Using multiple Specc1l mouse alleles, we have established that loss of SPECC1L leads to a delay in palatal shelf elevation. Interestingly, in-frame CCD2 specific mutations (deletions, point mutations) in mice result in a more severe palatal shelf elevation delay, indicating a gain-of-function. At the cellular level, CCD2 leads to perinuclear mislocalization of SPECC1L along with a disruption of cytoplasmic filamentous actin and non-muscle myosin II. Lastly, our preliminary data show that cleft palate in CCD2 mutants is rescued upon maternal folic acid supplementation. In Aim 1, we will study the cell and tissue mechanics underlying both normal and abnormal palate elevation in CCD2 alleles using ex vivo and in vivo magnetic resonance imaging and computational modeling. In Aim 2, we will investigate the cellular and molecular mechanisms underlying the gain-of-function in CCD2 mutant cells using state-of-the-art proteomic analyses. In Aim 3, we will determine how maternal folate supplementation rescues palate elevation defects in CCD2 mutants. Successful completion of these studies will provide critical insights into tissue dynamics and cell signaling during normal and abnormal palatal shelf elevation, as well as into the effect of maternal folic acid supplementation, which will provide targets for future translational strategies against orofacial clefting.


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 = $604,187 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Oral Diseases and Disorders Research	000	4	6/16/2026	NON-COMPETING CONTINUATION	$604,187
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Oral Diseases and Disorders Research	001	4	7/14/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $604,187

Issue Date FY: 2025 ( Subtotal = $607,109 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Oral Diseases and Disorders Research	000	3	7/31/2025	NON-COMPETING CONTINUATION	$607,109
														Subtotal = $607,109

Issue Date FY: 2024 ( Subtotal = $596,710 )
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	5/15/2024	NON-COMPETING CONTINUATION	$596,710
														Subtotal = $596,710

Issue Date FY: 2023 ( Subtotal = $576,790 )
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	8/10/2023	NEW	$576,790
														Subtotal = $576,790

Grand Total All Awards = $2,384,796

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Role of SPECC1L cytoskeletal protein in palate elevation dynamics

Award Number: R01DE032825

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: 08/10/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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