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Cell cycle regulation in the cephalic epithelium as a driver of midface morphogenesis

Award Number: F31DE032561
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: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 06/14/2024

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Cell cycle regulation in the cephalic epithelium as a driver of midface morphogenesis - PROJECT SUMMARY Cleft lip with or without cleft palate (CL/P) is the most common craniofacial birth defect in humans. During embryogenesis, the medial, lateral, and maxillary prominences of the midface must fuse at a site called the λ junction to form the upper lip and primary palate. Previously, our lab discovered roles of the midface epithelium during fusion, including: 1) the coordination of epithelial dissolution via two discreet cell populations undergoing apoptosis and epithelial-to-mesenchymal transition; 2) in murine models of CL/P deficient in PBX genes these epithelial subpopulations are absent; and 3) only half of the epithelial cells removed were accounted for by these processes. This led our lab to investigate further the presence of novel subpopulations in the midface epithelium. In performing single cell RNA sequencing of mouse midface epithelium alone, during fusion stages, several subpopulations were identified and validated in vivo. I found that one subpopulation possessed a unique transcriptomic signature wherein enrichment for cell cycle arrest genes and depletion of cell cycle progression gene transcripts coincided with the expression of genes implicated in mouse and human CL/P pathogenesis. My in vivo analysis found this subpopulation of cells was spatio-temporally localized to the site of λ fusion, leading us to name these cells “λ fusion effectors.” I hypothesize that the λ fusion effectors are implicated in the pathogenesis of CL/P and that cell cycle arrest is a yet uncharacterized mechanism tied to prominence fusion. To better understand this epithelial subpopulation and the role that the cell cycle plays during midface fusion, I propose to 1: Assess and track cell cycle progression and arrest in λ fusion effector cells during upper lip/primary palate morphogenesis and fusion in wild type conditions. I will assess subpopulation dynamics in vivo by conducting EdU/BrdU dual labeling of mouse embryos and I will track cell cycle phase changes ex vivo by using an explant system from FUCCI mouse embryos. 2: Establish the molecular mechanisms underlying cell cycle arrest in λ fusion effector cells during upper lip/primary palate morphogenesis and fusion in wild type conditions. I will isolate and quantify λ fusion effector cells from the distal prominence tips using cytometry approaches and will identify PBX1 gene targets, with a focus on cell cycle arrest genes, in the isolated subpopulation of λ fusion effector cells versus neighboring λ epithelium. Aim 3: Determine if, in our mouse model of CL/P, embryos with compound loss of Pbx1/2 exhibit changes to cell cycle arrest in the epithelial λ fusion effector subpopulation. I will quantify and assess perturbations in the λ fusion effector cell subpopulation in Pbx1/2 mutants with CL/P. My research will investigate the molecular mechanism of cell cycle arrest during fusion of the λ junction and how it pertains to CL/P pathogenesis. Given the genetic links of this subpopulation to human CL/P, it is my hope that this study will provide novel targets for CL/P early prenatal diagnosis, prevention and treatment, and uncover mechanisms of cell cycle arrest with broad implications in tissue fusion, repair and morphogenesis.


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 = -$39,300 )
2025	2024	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	10/17/2024	NON-COMPETING CONTINUATION	-$22,445
2025	2024	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	4/24/2025	NON-COMPETING CONTINUATION	-$16,855
														Subtotal = -$39,300

Issue Date FY: 2024 ( Subtotal = $46,411 )
2024	2024	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	6/17/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	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	2/9/2024	NON-COMPETING CONTINUATION	$45,131
														Subtotal = $46,411

Issue Date FY: 2022 ( Subtotal = $43,587 )
2022	2022	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	8/30/2022	NEW	$43,587
2022	2022	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	001	1	8/30/2022	NEW	$0
														Subtotal = $43,587

Grand Total All Awards = $50,698

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Cell cycle regulation in the cephalic epithelium as a driver of midface morphogenesis

Award Number: F31DE032561

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: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 06/14/2024

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