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The Molecular Basis of Nasal Pit Morphogenesis and its Role in Upper Lip Formation

Award Number: F30DE033613
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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The Molecular Basis of Nasal Pit Morphogenesis and its Role in Upper Lip Formation - Project Summary/Abstract While cleft lip, with or without cleft palate, is one of the most common craniofacial birth defects, the molecular and cellular etiology of the phenotype is incompletely understood, and the fundamental morphogenesis that underlies upper lip formation remains largely mysterious. This is in part due to a complex three-dimensional topology of the developing midface over a series of several days during mid-gestation. At the onset of lip development, the frontonasal process (FNP) cranial ectoderm undergoes substantial morphological change starting with bilateral thickening and formation of the epithelial nasal placodes, which undergo invagination to form nasal pits, separating the medial nasal processes (MNP) from the lateral nasal processes (LNP). Fusion of the MNP and the LNP encloses the nasal canals and initiates the formation of the upper lip, which also involves fusion of the MNP and maxillary process (MXP). While some studies have focused on the regulation of these final fusion steps, much less attention has been paid to the cellular drivers and molecular regulators of the significant preceding morphologic changes during nasal pit formation as it contributes to proper lip formation. Previous reports together with preliminary data presented here, demonstrate that loss of TGFβ Receptor I (Alk5) within the craniofacial ectoderm leads to cleft lip. TGFβ signaling via TGFβRI can activate both canonical and/or noncanonical downstream signaling pathways in a context specific manner, leading to transcriptional and/or cytoskeletal changes critical in many tissue morphogenesis events. Disruption of TGFβRI or actomyosin contractility through the compound loss of the two major mammalian embryonic non-muscle myosins, NMIIA and NMIIB, results in cleft lip and defects in early nasal pit morphogenesis. This project will test the central hypothesis that nasal pit morphogenesis, driven in part by tissue bending driven by actomyosin contractility, causes conformational changes that bring the MNP/LNP/MXP in proximity for fusion and establish midface structure, and that signaling via TGFβRI is a key regulator of this process. Aim 1 will establish the cellular dynamics driving nasal pit morphogenesis as it contributes to lip formation. Aim 2 will determine how TGFβ signaling via TGFβRI drives nasal pit morphogenesis and lip formation. This study will be a key step in understanding how upper lip morphogenesis occurs, and the mechanisms underlying cleft lip.


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 = $55,914 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	3	4/16/2026	NON-COMPETING CONTINUATION	$576
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	1/20/2026	NON-COMPETING CONTINUATION	$55,338
														Subtotal = $55,914

Issue Date FY: 2025 ( Subtotal = $48,790 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	2	8/12/2025	NON-COMPETING CONTINUATION	$564
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	11/27/2024	NON-COMPETING CONTINUATION	$48,226
														Subtotal = $48,790

Issue Date FY: 2023 ( Subtotal = $45,632 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	9/12/2023	NEW	$45,632
														Subtotal = $45,632

Grand Total All Awards = $150,336

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The Molecular Basis of Nasal Pit Morphogenesis and its Role in Upper Lip Formation

Award Number: F30DE033613

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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