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Gene regulatory network controlling neural crest derived formation of facial cartilage

Award Number: R01DE024157
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: 06/01/2014
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Gene regulatory network controlling neural crest derived formation of facial cartilage - In the previous grant period, we explored regulatory differences between cranial and trunk neural crest cells. Comparative transcriptomics coupled with functional perturbation revealed a premigratory “cranial-specific” neural crest GRN subcircuit that links anterior identity to ability to differentiate into facial cartilage. Here, we propose to elucidate the gene regulatory network (GRN) downstream of this cranial-specific subcircuit that confers ability to differentiate into facial skeleton. The goal is to understand the program underlying differentiation and pattern formation of craniofacial cartilage. First, we will explore regulatory changes in trunk neural crest cells after introduction of cranial crest subcircuit genes. Next, we will characterize late-migrating cranial crest cells as they condense to form facial cartilage at the single cell level to understand GRN changes as a function of time, at single cell resolution and a functional level. Finally, we propose to identify active enhancers and their direct inputs in late migrating and condensing cranial crest cells by combining in vivo electroporation of reporter constructs in the chick embryo with high throughput genomic approaches. To these ends, we will conduct the following aims: Specific Aim 1: Effects of “reprogramming” trunk neural crest cell identity. Ectopic expression of cranial crest subcircuit genes imbues trunk crest cells with chondrogenic potential after grafting to the head. Here we will: characterize transcriptional changes that occur in reprogrammed trunk crest cells over time; test the ability of reprogrammed trunk neural crest to form ectopic cartilage in their normal environment; test the ability of the cranial subcircuit to confer chondrogenic ability onto ES cells and crestosphere-derived cells. Specific Aim 2: Transcriptional profiling and functional validation of condensing cranial neural crest cells at high cell resolution using single cell RNA-seq and multiplex in situ hybridization. To gain insights into how neural crest-derived cells differentiate and what gene regulatory programs control their progression to facial skeleton, we propose to perform single cell RNA-seq of condensing cranial crest cells in the branchial arches with the goal of identifying candidate GRN components of the cartilage-forming module. We will validate expression of candidate transcription factors at high resolution and test their function using CRISPR-Cas9 knockout. Specific Aim 3: Construction of a cranial cartilage gene regulatory network (GRN) by identifying cis- regulatory elements and direct downstream targets of the cranial crest-specific subcircuit genes. In order to build regulatory linkages in branchial arch neural crest, we will characterize their chromatin landscape using low-input Assay for Transposase-Accessible Chromatin (ATAC-seq) optimized for as few as 1500 cells per replicate and perform CUT&RUN to confirm direct inputs downstream of subcircuit genes.


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 = $382,950 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	10	5/8/2025	NON-COMPETING CONTINUATION	$38,295
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	10	4/1/2025	NON-COMPETING CONTINUATION	$344,655
														Subtotal = $382,950

Issue Date FY: 2024 ( Subtotal = $375,291 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	9	6/18/2024	NON-COMPETING CONTINUATION	$30,636
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	3/12/2024	NON-COMPETING CONTINUATION	$344,655
														Subtotal = $375,291

Issue Date FY: 2023 ( Subtotal = $382,950 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	8	3/21/2023	NON-COMPETING CONTINUATION	$382,950
														Subtotal = $382,950

Issue Date FY: 2022 ( Subtotal = $379,121 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	7	2/23/2022	NON-COMPETING CONTINUATION	$344,655
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	7	4/21/2022	NON-COMPETING CONTINUATION	$34,466
														Subtotal = $379,121

Issue Date FY: 2021 ( Subtotal = $382,950 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	6	2/23/2021	COMPETING CONTINUATION	$382,950
														Subtotal = $382,950

Issue Date FY: 2020 ( Subtotal = -$2 )
2020	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	9/13/2020	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2018 ( Subtotal = $358,761 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	5	4/20/2018	NON-COMPETING CONTINUATION	$41,625
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	3/6/2018	NON-COMPETING CONTINUATION	$374,625
2018	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	4	3/6/2018	SUPPLEMENT FOR EXPANSION	-$57,489
														Subtotal = $358,761

Issue Date FY: 2017 ( Subtotal = $503,043 )
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	4	5/26/2017	NON-COMPETING CONTINUATION	$41,625
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	3/10/2017	NON-COMPETING CONTINUATION	$374,625
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	4	4/25/2017	SUPPLEMENT FOR EXPANSION	$86,793
														Subtotal = $503,043

Issue Date FY: 2016 ( Subtotal = $416,250 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	3/4/2016	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2015 ( Subtotal = $416,250 )
2015	2015	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	2/26/2015	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2014 ( Subtotal = $416,250 )
2014	2014	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	5/30/2014	NEW	$416,250
														Subtotal = $416,250

Grand Total All Awards = $4,013,814

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Gene regulatory network controlling neural crest derived formation of facial cartilage

Award Number: R01DE024157

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: 06/01/2014

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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