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Genetic and epigenetic mechanisms of FSHD pathogenesis

Award Number: R01AR071287
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Genetic and epigenetic mechanisms of FSHD pathogenesis - Abstract Facioscapulohumeral dystrophy (FSHD) is one of the most common muscular dystrophies in the U.S. Currently, there is no effective treatment, and the pathogenic process is still not completely understood. Most cases (>95%) of FSHD involve mono-allelic deletion of macrosatellite D4Z4 repeat sequences at the subtelomeric region of chromosome 4q (FSHD1), while the remaining ~5% of cases demonstrate no D4Z4 repeat contraction (FSHD2). Mutations in the SMCHD1 genes were linked to FSHD2, and also greatly exacerbate the phenotype of FSHD1 by acting as a modifier of the disease severity. Expression of the DUX4 gene encoded within the D4Z4 repeat is critically linked to the development of FSHD. Since overexpression of DUX4 is cytotoxic in human myocytes and mice, it is thought that DUX4-induced cytotoxicity is the cause of dystrophy. However, only ~0.1% of patient muscle cells appear to express DUX4, and DUX4 expression can occasionally be observed in muscle cells from unaffected individuals. It is not straightforward to study FSHD in model organisms as D4Z4 repeats and some of the critical DUX4 target genes are primate-specific. During the previous funding period, we found evidence that DUX4-negative patient myocytes exhibit altered gene expression distinct from control myocytes and cross-regulation of DUX4 target transcription factors contributing to sustaining the DUX4 gene network. These findings strongly argue that FSHD mechanism is not simply DUX4-induced cell killing and further investigation is necessary to understand FSHD pathogenesis. We also developed genetically engineered mutant myoblast lines carrying D4Z4 deletion, SMCHD1 mutation or both to simulate FSHD1, FSHD2 and severe cases of FSHD1, respectively and began to characterize epigenetic and gene expression consequences of defined mutations in the isogenic background. Specific Aims of this project are (1) to create additional mutant clones to interrogate the consequences of FSHD mutations in different muscles with different disease susceptibility and during early myogenesis; (2) to investigate dynamics and regulation of DUX4 and target gene expression, and (3) to identify a modifier gene(s) that dictates disease susceptibility and severity. The successful outcome of the project should reveal DUX4 and target gene dynamics and their contributions to FSHD pathogenesis and identify critical determinants for the disease susceptibility, which may lead to identification of potentially new therapeutic targets.


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 = $487,728 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/4/2025	NON-COMPETING CONTINUATION	$487,728
														Subtotal = $487,728

Issue Date FY: 2024 ( Subtotal = $486,138 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	5/29/2024	NON-COMPETING CONTINUATION	$486,138
2024	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	10/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $486,138

Issue Date FY: 2023 ( Subtotal = $505,724 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	5/31/2023	NON-COMPETING CONTINUATION	$505,724
2023	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	6/1/2023	COMPETING CONTINUATION	$75,389
2023	2021	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/1/2023	NON-COMPETING CONTINUATION	-$75,389
														Subtotal = $505,724

Issue Date FY: 2022 ( Subtotal = $427,505 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	9/1/2022	COMPETING CONTINUATION	$427,505
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $427,505

Issue Date FY: 2021 ( Subtotal = $433,082 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/29/2021	NON-COMPETING CONTINUATION	$433,082
														Subtotal = $433,082

Issue Date FY: 2020 ( Subtotal = $446,477 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/9/2020	NON-COMPETING CONTINUATION	$446,477
														Subtotal = $446,477

Issue Date FY: 2019 ( Subtotal = $446,477 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/21/2019	NON-COMPETING CONTINUATION	$446,477
														Subtotal = $446,477

Issue Date FY: 2018 ( Subtotal = $446,477 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/21/2018	NON-COMPETING CONTINUATION	$446,477
														Subtotal = $446,477

Issue Date FY: 2017 ( Subtotal = $455,277 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/30/2017	NEW	$455,277
														Subtotal = $455,277

Grand Total All Awards = $4,134,885

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Genetic and epigenetic mechanisms of FSHD pathogenesis

Award Number: R01AR071287

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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