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Genetic repair of muscular degeneration associated with Duchenne muscular dystrophy

Award Number: R15AR068583
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: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Genetic repair of muscular degeneration associated with Duchenne muscular dystrophy - Project Summary/Abstract: Duchenne Muscular dystrophy (Dmd) is a lethal degenerative disease affecting 1 in 5,000 males. Dmd is caused by mutations in the gene encoding dystrophin, a highly conserved protein linking muscle cell membranes with the extracellular matrix and the contractile machinery within them. Dystrophin has structural and signaling functions. Loss of dystrophin is linked to muscular and neural degeneration. While traditional analyses of mice, worms and other animals modeling Dmd genetically, through loss-of-function mutations in the dystrophin gene, resulted in great advances, these systems have only produced relatively mild muscular and behavioral phenotypes. To date there is no cure for Dmd. To model the acute muscle degeneration observed in Dmd patients in a model system amenable to genetics we developed a fast and inexpensive nematode assay. Our assay elicits strong behavioral and cellular phenotypes in dystrophic (dys-1) nematodes to a degree not previously attained in other systems. During our previous award cycle, we improved our assay to allow automatization and medium to high throughput screening of candidate treatments. We went on to characterize many dystrophic phenotypes and found that they first arise during embryogenesis. We also identified the first neurological impairments in dystrophic worms, where the sensory function of ASH neurons is impaired. A suppressor mutant, and an RNA-interference screen both pointed to calmodulin as a therapeutic target. The first specific aim of this project is to characterize the onset of dystrophic phenotypes during myogenesis, and to separate the contribution of dystrophin’s signaling and structural roles to these deficits. This will identify the mechanism by which muscles become impaired during development. The second aim is to characterize the role dystrophin plays in the structure and function of the ASH neurons. These well-studied neurons will provide an amenable springboard to study the neuropathophysiology of Dmd. In the third aim, we will use our assay to identify downstream effectors of calmodulin responsible for the prevention of dystrophic phenotypes observed following reduction of calmodulin function in dys-1 animals. Identifying these effectors will be key to finding safe treatment avenues, sparing additional processes mediated by calmodulin. To validate our findings and bridge the gap to humans, we will use humanized dystrophic nematodes and human myogenic cell lines. Completion of these aims will provide key insights into Dmd pathophysiology and identify new molecular targets and pathways that can be used to treat this disease.


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 = $0 )
2024	2022	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	CAMPUS BOX 1100	NORMAL	IL	61790	MCLEAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/1/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $375,393 )
2022	2022	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	302 HOVEY HALL	NORMAL	IL	61790	MCLEAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/22/2022	COMPETING CONTINUATION	$375,393
														Subtotal = $375,393

Issue Date FY: 2021 ( Subtotal = -$26 )
2021	2016	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	302 HOVEY HALL	NORMAL	IL	61790	MCLEAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/4/2020	NEW	-$26
														Subtotal = -$26

Issue Date FY: 2016 ( Subtotal = $403,109 )
2016	2016	ILLINOIS STATE UNIVERSITY	1200 COMPTROLLERS OFFICE	NORMAL	IL	61790	MCLEAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/19/2016	NEW	$403,109
														Subtotal = $403,109

Grand Total All Awards = $778,476

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Genetic repair of muscular degeneration associated with Duchenne muscular dystrophy

Award Number: R15AR068583

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: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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