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In Toto Readout of Transcriptomes and Lineage Relationships in Native Craniofacial Tissues

Award Number: R01DE034294
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: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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In Toto Readout of Transcriptomes and Lineage Relationships in Native Craniofacial Tissues - PROJECT SUMMARY In response to Notice of Special Interest (NOSI): Single-Cell Level Spatiotemporal Mapping of Dental and Craniofacial Embryogenesis (NOT-DE-22-003), we propose innovative new technology to comprehensively map the transcriptomes and lineage histories of all cell types in the vertebrate face, and how these are altered in congenital anomalies and adult repair. Current lineage tracing techniques lack the ability to define all cell relationships at single-cell resolution in complex vertebrate tissues such as the face. The cranial neural crest- derived mesenchyme generates the majority of skeletal and connective tissues of the face, yet we still have an incomplete picture of the diversity of mesenchymal progenitors, whether there is a hierarchy or continuum of cell fate decisions, and whether lineages vary across the face to generate diverse structures. To do so requires new ways to label every cell uniquely and permanently in the developing face, and then to read out shared lineage histories and cell type information in the context of native tissue. This proposal aims to achieve this through a cross-disciplinary collaboration between zebrafish (Gage Crump) and mouse (Amy Merrill) craniofacial experts at the University of Southern California and a systems biologist (Michael Elowitz) at the California Institute of Technology. As zebrafish and mouse are powerful and complementary models for craniofacial disease research, we will use seqFISH technology to map the transcriptomes of all cell types of the developing face in both species. We will then use a new type of MEMOIR lineage barcoding technique developed by PI Elowitz that allows lineage histories to be read out together with transcriptomes by seqFISH while preserving spatial context. Integration of seqFISH and MEMOIR will allow us to comprehensively define all craniofacial cell types and their lineage relatedness from the time of barcoding. Analysis of lineage histories of the normal fish and mouse face will reveal the types of lineage relationships, how they vary across the face, and the extent to which they are conserved across vertebrates. Next, we will apply MEMOIR to complementary zebrafish and mouse Nr5a2 mutant models, which we showed have altered ratios of skeletal and connective tissue types in the jaw. Global analysis of altered lineage relationships in mutants will reveal the types of lineage decisions controlled by the Nr5a2 nuclear receptor and the extent to which its role has evolved from fish to mammals. We will also use MEMOIR to understand the degree to which reprogramming of cell identity may underlie the ability of zebrafish to robustly regenerate bone and cartilage in the adult jaw. In particular, we will compare the extent to which different injuries induce distinct types of lineage plasticity to replace the correct missing cell types. In the future, stimulating lineage plasticity in mammals may represent a novel strategy to boost endogenous repair of non-healing injuries. More broadly, our project will serve as a paradigm for globally defining lineage relationships in diverse craniofacial tissues in the context of normal development, genetic disease, and adult repair.


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 = $672,179 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	2	6/11/2026	NON-COMPETING CONTINUATION	$672,179
2026	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	6/8/2026	NEW	$0
														Subtotal = $672,179

Issue Date FY: 2025 ( Subtotal = $688,679 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	7/22/2025	NEW	$688,679
														Subtotal = $688,679

Grand Total All Awards = $1,360,858

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In Toto Readout of Transcriptomes and Lineage Relationships in Native Craniofacial Tissues

Award Number: R01DE034294

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: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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