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Investigating proteostasis in facioscapulohumeral muscular dystrophy

Award Number: R21AR080887
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Investigating proteostasis in facioscapulohumeral muscular dystrophy - ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder caused by complex genetic and epigenetic mechanisms. Previous studies showed that transcription de- repression of double homeobox protein 4 (DUX4) due to epigenetic changes in the D4Z4 region causes FSHD. The epigenetic changes are caused by either contraction of the D4Z4 array from 11-150 repeat units in unaffected individuals to 1-10 repeat units in roughly 95% of patients (FSHD1), or mutations in epigenetic regulators of the D4Z4 region (FSHD2). The expression of DUX4 leads to downstream molecular and cellular changes, which contribute to disease progression. Previous studies reported defects in protein degradation process in FSHD, however what proteins are affected and whether protein synthesis is affected is not clear. To study the dynamic changes in protein abundance in affected muscle cells, the research team conducted a preliminary study using liquid chromatography - tandem mass spectrometry in combination with metabolic labelling. The study identified distinct protein profiles between the myoblasts from individuals affected by FSHD and their unaffected siblings. We hypothesize that DUX4 expression is responsible for the disturbance of protein homeostasis, which contributes to the downstream molecular and cellular defects observed in FSHD. In the proposed study, we will first study the protein synthesis and degradation in immortalized FSHD myoblasts before and after a DUX4-reducing treatment. In aim 2, we will validate the in vitro findings using a xenograft mouse model. This project will discover proteins that are mis-regulated by degradative processes and synthetic processes in FSHD, which may open new opportunities for therapeutic development. The findings will also provide new insights of the disease mechanisms and evaluate the efficacy of a DUX4-reducing treatment using antisense oligonucleotides targeting the DUX4.


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 = -$61 )
2026	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/16/2025	NON-COMPETING CONTINUATION	-$61
														Subtotal = -$61

Issue Date FY: 2023 ( Subtotal = $202,322 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/10/2023	NON-COMPETING CONTINUATION	$202,322
														Subtotal = $202,322

Issue Date FY: 2022 ( Subtotal = $180,322 )
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/23/2022	NEW	$180,322
														Subtotal = $180,322

Grand Total All Awards = $382,583

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Investigating proteostasis in facioscapulohumeral muscular dystrophy

Award Number: R21AR080887

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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