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Molecular and Cellular Basis of Craniosynostosis

Award Number: R01DE026339
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: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Molecular and Cellular Basis of Craniosynostosis - During fetal development and early childhood, growth of the bony skull accommodates a rapid expansion of the underlying brain. This is accomplished first by progenitors that grow the individual skull bones, and then by stem cells residing in the flexible bony joints called sutures. In a common birth defect called craniosynostosis (1 in 2000 live births), loss of the cranial sutures results in bony fusions that impede brain growth, thus leading to cognitive impairment if left untreated. Surgical correction involves invasive and risky surgeries on infants to break apart the fused bones. Unfortunately, the skull bones often re-fuse, necessitating repeated surgeries. There is thus a critical need to better understand the causes of craniosynostosis, such that we can develop therapies that minimize repeated surgical interventions. In the previous funding cycle, we generated and characterized the first zebrafish model of Saethre-Chotzen Syndrome, which preferentially affects the coronal suture. In so doing, we pinpointed early changes in the growth rates of the embryonic skull bones as a major cause of suture fusions. In this renewal we address three outstanding questions in the field of craniosynostosis. In Aim 1, we investigate the embryonic origins of the suture stem cells that grow and maintain the skull. While suture stem cells have been studied at postnatal stages, whether they arise from progenitors at the tips of growing bones, or alternatively from migrating cells, remains debated. By generating the first single-cell transcriptomes of the developing mouse and zebrafish coronal sutures, we have uncovered conserved embryonic cell types and molecular markers for suture progenitors. Using new lineage tracing tools in mouse and fish, we will test that bone front progenitors expressing ETS-family transcription factors are the origin of suture-resident stem cells. In Aim 2, we investigate how the Saethre-Chotzen genes Twist1 and Tcf12 regulate the transition from bone front progenitors to suture stem cells. Preliminary data reveal that Twist1 and Tcf12 upregulate the Bmp antagonists Grem1 and Noggin during suture formation, suggesting that tighter regulation of Bmp signaling is essential to slow bone growth and prevent fusions. Using mouse conditional genetics and new zebrafish mutants, we will test that direct regulation of Grem1 and Noggin expression by Twist1 and Tcf12 is necessary and sufficient for regulated bone growth and normal suture formation. In Aim 3, we address a central mystery of the craniosynostosis field – why do particular mutations tend to affect only particular sutures? By generating and contrasting new zebrafish models for 11 coronal and 7 midline craniosynostosis genes, we will test whether coronal suture formation is particularly sensitive to mutations that perturb the rate of bone growth. To do so, we will make use of new zebrafish transgenic reporters that allow quantitative in vivo measurements of osteoblast addition and suture formation. A strength of the proposal is the unique team of experts in zebrafish, mouse, and human craniofacial genetics. By using model organisms to understand the developmental bases for diverse types of craniosynostosis, we strive toward developing more targeted treatments for craniosynostosis patients with particular genetic mutations.


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 = $596,155 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	7/9/2024	NON-COMPETING CONTINUATION	$596,155
														Subtotal = $596,155

Issue Date FY: 2023 ( Subtotal = $616,571 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	8	7/11/2023	NON-COMPETING CONTINUATION	$616,571
2023	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	7	1/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $616,571

Issue Date FY: 2022 ( Subtotal = $619,877 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	004	7	6/23/2022	NON-COMPETING CONTINUATION	$619,877
2022	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	6	5/5/2022	COMPETING CONTINUATION	$122,106
2022	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	6	11/9/2021	COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	6	11/4/2021	COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	5	5/5/2022	NON-COMPETING CONTINUATION	-$122,106
														Subtotal = $619,877

Issue Date FY: 2021 ( Subtotal = $618,769 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	6	9/23/2021	COMPETING CONTINUATION	$618,769
2021	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	9/22/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $618,769

Issue Date FY: 2020 ( Subtotal = $492,885 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	5	4/23/2020	NON-COMPETING CONTINUATION	$669,383
2020	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	4	4/23/2020	NON-COMPETING CONTINUATION	-$88,249
2020	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	4/23/2020	NON-COMPETING CONTINUATION	-$88,249
2020	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	4/23/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $492,885

Issue Date FY: 2019 ( Subtotal = $761,592 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	3/11/2019	NON-COMPETING CONTINUATION	$761,592
														Subtotal = $761,592

Issue Date FY: 2018 ( Subtotal = $761,592 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	4/20/2018	NON-COMPETING CONTINUATION	$76,161
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	3/8/2018	NON-COMPETING CONTINUATION	$685,431
														Subtotal = $761,592

Issue Date FY: 2017 ( Subtotal = $758,952 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	2	5/26/2017	NON-COMPETING CONTINUATION	$67,072
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	2	3/14/2017	SUPPLEMENT FOR EXPANSION	$88,249
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	3/10/2017	NON-COMPETING CONTINUATION	$603,631
														Subtotal = $758,952

Issue Date FY: 2016 ( Subtotal = $659,998 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	6/28/2016	NEW	$659,998
														Subtotal = $659,998

Grand Total All Awards = $5,886,391

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Molecular and Cellular Basis of Craniosynostosis

Award Number: R01DE026339

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: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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