Thursday, April 25, 2024 4/25/2024

Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis

Award Number: R01AR079545
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

PROJECT SUMMARY Fibrosis is the accumulation of extracellular matrix components that disrupt tissue function and is prevalent across many muscle diseases. Muscle functions compromised in fibrosis include muscles primary function to contract as well as its ability to be compliantly stretched when not active. This results in weak and stiff muscle decreasing mobility and producing joint contractures. Skeletal muscle regenerates following injury from resident muscle stem cells, however those cells are sensitive to the organization and mechanics of fibrotic extracellular matrix. Another muscle resident stem cell, fibro-adipogenic progenitors, support myogenesis following injury, but in the context of fibrosis contribute to the pathologic buildup of extracellular matrix. However, the sensitivity of fibro-adipogenic progenitors to their mechanical environment is unknown. Nor is it known how fibro-adipogenic progenitors production of extracellular matrix signals to muscle stem cells to support or impair myogenesis. In order to target effective anti-fbrotic therapies the mechanisms that of communication between fibro-adipogenic progenitors and the extracellular matrix that defines fibrosis must be revealed. Further, the fibrotic environment can act as a barrier to restorative gene therapies for muscular dystrophy, but how fibrosis may influence the efficacy of promising gene therapies is unknown. Fibrosis is particularly common in Duchenne muscular dystrophy, with associated joint contractures. Yet, even removal of functional dystrophin from more fibrotic mouse strains yields a less severe fibrosis, motivating a conjunction of studies in both mice and humans. Fibro-adipogenic progenitors can be activated into pro- fibrogenic cells to resist apoptotic signals and produce excessive extracellular matrix components. This fibrotic extracellular matrix is mainly made of fibrillar collagen, which is the dominant load-bearing structure within healthy and fibrotic extracellular matrix. However, the organization of collagen fibers in the extracellular matrix can alter both the mechanics and adherent cell phenotypes. Fibro-adipogenic progenitors are similar to mesenchymal stromal cells, yet how extracellular matrix organization and mechanical signals drive conversion to the pro-fibrotic state are not known. Nor is it known how one of the primary functions of fibro-adipogenic progenitors, to secrete extracellular matrix, impacts the muscle stem cells responsible for myogenesis. This the potential to create a positive feedback cycle between fibro-adipogenic protenitors and the extracellular matrix. Promising gene therapy using micro-dystrophin is able to largely restore the integrity of myofibers. However, it isn’t known if once the pro-fibrotic cycle is in place if restoring the myofiber integrity and the initiating signals of fibrosis will be sufficient to reverse prominent fibrosis and the associated decline in function. Thus, our objective is to reveal fibro-adipogenic progenitors-based extracellular matrix contribution to functional decline and lack of regeneration in fibrosis along with the potential to reverse fibrosis in muscular dystrophy. In Aim 1, we will utilize a combination of engineered gels and native decellularized matrices to mimic health and fibrosis to determine both the architectural and mechanical features of a cell substrate that directs fibro- adipogenic progenitor fate. In Aim 2, we will induce pro-fibrotic or pro-regenerative fibro-adipogenic progenitor synthesis of extracellular matrices to determine how their structure influences muscle stem cell myogenesis in fibrosis. In Aim 3, micro-dystrophin gene therapy will be administered to before and after the onset of fibrosis to stratify the functional efficacy and change in fibrosis based on the initial stage of fibro-adipogenic progenitors and fibrosis. Success in these Aims will establish the mechanisms fibro-adipogenic progenitors and extracellular matrix interact to perpetuate progressive fibrosis and identify specific targets for anti-fibrotic therapy development that can restore function and enhance the efficacy of restorative gene therapy in muscular dystrophies.


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 = $410,999 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/18/2024	NON-COMPETING CONTINUATION	$410,999
														Subtotal = $410,999

Issue Date FY: 2023 ( Subtotal = $461,780 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/28/2023	NON-COMPETING CONTINUATION	$461,780
														Subtotal = $461,780

Issue Date FY: 2022 ( Subtotal = $472,819 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	5/2/2022	NEW	$0
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/5/2022	NEW	$472,819
														Subtotal = $472,819

Grand Total All Awards = $1,345,598

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis

Award Number: R01AR079545

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer