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Skeletal stem cell plasticity in craniofacial bone diseases.

Award Number: R35DE034348
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: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2032

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Skeletal stem cell plasticity in craniofacial bone diseases. - Project Summary / Abstract Bones in the craniofacial complex are susceptible to various disease conditions due to sustained functional demand associated with essential activities for survival, such as mastication, respiration, and swallowing. Craniofacial bones are highly adaptable to external forces, as exemplified by the classical functional matrix hypothesis; paradoxically, craniofacial bones have limited inherent regeneration potential. While significant progress has been made in unraveling mechanisms of congenital craniofacial bone deformities, there is a fundamental gap in knowledge regarding how craniofacial formation is dynamically regulated in response to incessant functional demand in later life. This gap leads to an insufficient understanding of the mechanisms of craniofacial bone diseases that clinicians commonly observe in dental practice settings. Dr. Noriaki Ono is an orthodontist-scientist and a mid-career bone biologist with a steadfast focus on skeletal stem cells and bone development, with a highly productive research program and a substantial track record of contribution to the bone research field. The overall vision is to establish a craniofacial bone disease program focusing on skeletal stem cell plasticity as a central mechanism of craniofacial bone formation in intramembranous and endochondral pathways. This proposal aims to develop a research program to address fundamental mechanisms of craniofacial bone diseases from the perspective of skeletal stem cells and their lineage plasticity. The proposed research program will capitalize on the team's established expertise in mouse genetic in vivo lineage-tracing approaches and collaborations with single-cell computational biologists. Program 1: The first program investigates craniofacial skeletal stem cells in the intramembranous pathway. We will interrogate the fates and functions of periosteal and endosteal stem cells using intersectional genetic approaches to define how these cells contribute to bone formation in load-bearing craniofacial bones under normal and regenerative conditions. Program 2: The second program investigates craniofacial chondrocyte plasticity in the endochondral pathway. We will use high-dimensional single-cell level spatial transcriptomics to define mechanisms regulating chondrocyte plasticity in the cranial base synchondrosis and mandibular condylar cartilage. Program 3: The third program capitalizes on two novel craniofacial bone disease models of idiopathic condylar resorption (endochondral) and osteonecrosis of the jaw (intramembranous) induced by genetic manipulation in resident stem cell populations. We will delve into in-depth molecular and cellular mechanisms governing skeletal stem cell plasticity in load-bearing craniofacial bones and how its dysregulation leads to these disease conditions. The avenue for future clinical translation will be laid with highly collaborative oral and maxillofacial surgeons at UTHealth Houston. Together, these research programs are expected to establish skeletal stem cell dysregulation as a fundamental tenet of craniofacial bone diseases, which will serve as a critical therapeutic target of clinically prevalent conditions in autotherapies.


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 = $1,013,998 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	2	6/30/2025	NON-COMPETING CONTINUATION	$1,013,998
2025	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	1	10/28/2024	NEW	$0
														Subtotal = $1,013,998

Issue Date FY: 2024 ( Subtotal = $1,027,998 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	1	9/20/2024	NEW	$1,027,998
														Subtotal = $1,027,998

Grand Total All Awards = $2,041,996

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Skeletal stem cell plasticity in craniofacial bone diseases.

Award Number: R35DE034348

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: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2032

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