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Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy

Award Number: R01AR055686
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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Summary Many muscular dystrophies are caused by mutation in proteins that compromise the stability and integrity of the muscle sarcolemma, which results in high serum level of muscle enzymes such as Creatine Kinase. Understanding the mechanism by which healthy myofibers maintain their sarcolemmal integrity would enable development of new therapies for these muscular dystrophies. Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by mutations in dysferlin gene are such diseases. We have identified that loss of sarcolemmal integrity in LGMD2B muscle fibers is due to the delay in fusion of lysosome with the injured sarcolemma. This causes a delay in injury-triggered secretion of the lysosomal enzyme acid sphingomyelinase. Providing extracellular sphingomyelinase reverses the repair deficit and offers a potential therapy for LGMD2B. However, the mechanism by which alteration in sphingomyelin and other cell membrane lipids facilitates repair of injured muscle cell membranes has not been fully elucidated. This proposal aims to identify how lipids and lipid modifying enzymes such as acid sphingomyelinase facilitate maintenance of sarcolemmal integrity and facilitate repair of injured sarcolemma. We will achieve this by visualizing and modifying lipid composition of healthy muscle cell membrane and assess their effect on sarcolemmal integirty. We will also assess how lipids respond are altered in the LGMD2B patient and mouse muscle cells to identify potential therapeutic interventions to address these alterations. One such intervention we have established is the use of acid sphingomyelinase and we will evaluate its preclinical therapeutic potential for LGMD2B. These studies will not only help understand the role of lipids in maintenance of sarcolemmal integrity, but also provide insight into developing novel therapies for muscular dystrophies that move beyond targeting the proteins to also targeting the sarcolemmal lipids.


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: 2021 ( Subtotal = $371,128 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	6/4/2021	NON-COMPETING CONTINUATION	$371,128


Issue Date FY: 2020 ( Subtotal = $382,607 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/10/2020	NON-COMPETING CONTINUATION	$382,607


Issue Date FY: 2019 ( Subtotal = $382,607 )
2019	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/25/2019	NON-COMPETING CONTINUATION	$382,607


Issue Date FY: 2018 ( Subtotal = $384,375 )
2018	2018	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	6/27/2018	NON-COMPETING CONTINUATION	$384,375


Issue Date FY: 2017 ( Subtotal = $397,339 )
2017	2017	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	7/26/2017	COMPETING CONTINUATION	$397,339


Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/22/2014	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2012 ( Subtotal = $323,668 )
2012	2012	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	5/22/2012	NON-COMPETING CONTINUATION	$323,668


Issue Date FY: 2011 ( Subtotal = $323,668 )
2011	2011	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/27/2011	NON-COMPETING CONTINUATION	$323,668


Issue Date FY: 2010 ( Subtotal = $356,951 )
2010	2010	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	6/10/2010	NON-COMPETING CONTINUATION	$337,154
2010	2009	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	2/26/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$258,098
2010	2009	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/26/2010	NON-COMPETING CONTINUATION	-$238,301


Issue Date FY: 2009 ( Subtotal = $319,146 )
2009	2009	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/29/2009	NON-COMPETING CONTINUATION	$319,146


Issue Date FY: 2008 ( Subtotal = $314,688 )
2008	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/1/2008	NEW	$314,688


Grand Total All Awards = $3,556,177

Sum of Action Amount is $3,556,177;

Grand Total = $3,556,177

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Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy

Award Number: R01AR055686

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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