Wednesday, February 5, 2025 2/5/2025

Developmental regulation of cranial tendon fibroblast diversity and ECM interactions

Award Number: R01AR067797
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Tendons and ligaments are fundamental components of a functional musculoskeletal system. Tendons attach muscles to bone and interact with these tissues at distinct attachment sites called entheses (bone) and myotendinous junctions (MTJs, muscle). These interactions cause unique changes in gene expression and extracellular matrix (ECM) production that allow tendons to bear the forces exerted by muscle contraction. Transcription factors such as Scleraxis (Scx) specify early tendon progenitor cells (TPCs) and regulate ECM production. We previously discovered a critical ECM scaffolding protein called Thrombospondin-4b (Tsp4b) in zebrafish that is regulated by Scx, required for tendon maintenance and conserved in human tendons. How different types of tendon fibroblasts (tenocytes) are specified and influence ECM assembly at entheses or MTJs remains unclear. The current proposal addresses these issues using the advantages of the zebrafish for single cell RNA sequencing, in vivo imaging and genetic manipulation. The long-term goal of the proposed research is to understand the spatial dynamics of gene regulation and ECM assembly in tendons/ligaments and their regulation by mechanical force. Three primary hypotheses guide the research: 1) distinct subtypes of TPCs develop at entheses and MTJs in response to force, 2) ECM secreted by tenocytes regulates force-dependent signals that alter these distinct modes of gene expression in tenocytes and 3) retinoic acid is a novel force-dependent signal controlling tendon development. Aim 1 will perform scRNA-seq in tenocytes and see how force alters gene expression profiles. Aim 2 will study roles for Tsp4b, ECM, and TGF-beta signaling in force-dependent gene expression in tendons. Aim 3 will study the roles of RA signaling in tendons, and its responses to mechanical load. Each aim combines novel single cell approaches, genetic manipulation, live imaging and quantitative methods for physiological stimulation of muscles to get at mechanisms of tendon cell specification and ECM assembly in response to force.


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 = $339,943 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	12/12/2024	NON-COMPETING CONTINUATION	$339,943
														Subtotal = $339,943

Issue Date FY: 2024 ( Subtotal = $366,382 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	6/18/2024	NON-COMPETING CONTINUATION	$26,439
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	12/12/2023	NON-COMPETING CONTINUATION	$339,943
														Subtotal = $366,382

Issue Date FY: 2023 ( Subtotal = $377,714 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	1/10/2023	NON-COMPETING CONTINUATION	$339,943
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	5/11/2023	NON-COMPETING CONTINUATION	$37,771
														Subtotal = $377,714

Issue Date FY: 2022 ( Subtotal = $377,714 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	3/3/2022	COMPETING CONTINUATION	$377,714
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	7/15/2022	COMPETING CONTINUATION	$6
2022	2020	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	7/15/2022	NON-COMPETING CONTINUATION	-$6
														Subtotal = $377,714

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $339,900 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	3/31/2020	NON-COMPETING CONTINUATION	$33,990
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/25/2020	NON-COMPETING CONTINUATION	$305,910
														Subtotal = $339,900

Issue Date FY: 2019 ( Subtotal = $339,900 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	2/27/2019	NON-COMPETING CONTINUATION	$339,900
														Subtotal = $339,900

Issue Date FY: 2018 ( Subtotal = $305,910 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/28/2018	NON-COMPETING CONTINUATION	$305,910
														Subtotal = $305,910

Issue Date FY: 2017 ( Subtotal = $339,900 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/14/2017	NON-COMPETING CONTINUATION	$33,990
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/17/2017	NON-COMPETING CONTINUATION	$305,910
														Subtotal = $339,900

Issue Date FY: 2016 ( Subtotal = $339,900 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/5/2016	NEW	$339,900
														Subtotal = $339,900

Grand Total All Awards = $3,127,263

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Developmental regulation of cranial tendon fibroblast diversity and ECM interactions

Award Number: R01AR067797

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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