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Structure-Function Analysis of Sarcospan

Award Number: R01AR048179
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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PROJECT ABSTRACT Loss of muscle cell adhesion is emerging as a common theme in muscular dystrophies. In skeletal muscle, the dystrophin-glycoprotein complex is located at the sarcolemma and is composed of peripheral and integral membrane proteins. As a whole, this complex links the extracellular matrix to the intracellular actin cytoskeleton and provides structural stability to the sarcolemma during muscle contraction. Duchenne muscular dystrophy, the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex. My research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have shown that sarcospan plays an important role in mediating protein interactions within this complex. Sarcospan affects communication between the dystrophin-glycoprotein complex and the extracellular matrix. Importantly, we demonstrate that mild sarcospan over-expression in mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of compensatory proteins that is functionally analogous to the dystrophin-glycoprotein complex, including a7b1 integrin. The current 4R01 proposal builds on discoveries made during the prior funding periods by interrogating specific mechanisms by which sarcospan ameliorates disease in dystrophin- deficient mdx mice. We will test the hypothesis that sarcospan enhances a7b1 integrin outside-in and inside- out signaling. We will investigate the extracellular matrix of mdx muscle that is overexpressing sarcospan to determine how sarcospan affects the composition, organization, and mechanical properties of the extracellular matrix. Lastly, we will use our decellularization protocol to isolate the extracellular matrix and test its interaction with human iPSC-derived skeletal muscle progenitors to test principles of bidirectional communication in a newly developed in vitro model system. We expect that our results will illuminate molecular pathways that counter a broad range of muscle wasting disorders due to loss of extracellular matrix contact.


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: 2023 ( Subtotal = $343,200 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	6/23/2023	NON-COMPETING CONTINUATION	$343,200
														Subtotal = $343,200

Issue Date FY: 2022 ( Subtotal = $339,768 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	5/16/2022	NON-COMPETING CONTINUATION	$339,768
														Subtotal = $339,768

Issue Date FY: 2021 ( Subtotal = $332,904 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	5/24/2021	NON-COMPETING CONTINUATION	$332,904
														Subtotal = $332,904

Issue Date FY: 2020 ( Subtotal = $343,200 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	17	6/16/2020	NON-COMPETING CONTINUATION	$343,200
2020	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	16	11/30/2019	COMPETING CONTINUATION	$55
2020	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	11/30/2019	NON-COMPETING CONTINUATION	-$55
														Subtotal = $343,200

Issue Date FY: 2019 ( Subtotal = $338,272 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	7/18/2019	COMPETING CONTINUATION	$338,272
														Subtotal = $338,272

Issue Date FY: 2018 ( Subtotal = $387,530 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	7/6/2018	NON-COMPETING CONTINUATION	$387,530
														Subtotal = $387,530

Issue Date FY: 2017 ( Subtotal = $360,426 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	7/12/2017	NON-COMPETING CONTINUATION	$360,426
														Subtotal = $360,426

Issue Date FY: 2016 ( Subtotal = $369,913 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	6/21/2016	NON-COMPETING CONTINUATION	$369,913
														Subtotal = $369,913

Issue Date FY: 2015 ( Subtotal = $379,399 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	6/30/2015	NON-COMPETING CONTINUATION	$379,399
														Subtotal = $379,399

Issue Date FY: 2014 ( Subtotal = $418,335 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	7/7/2014	COMPETING CONTINUATION	$418,335
														Subtotal = $418,335

Issue Date FY: 2013 ( Subtotal = $301,896 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	1/28/2013	NON-COMPETING CONTINUATION	$286,006
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	7/11/2013	NON-COMPETING CONTINUATION	$15,890
														Subtotal = $301,896

Issue Date FY: 2012 ( Subtotal = $317,785 )
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	3/1/2012	NON-COMPETING CONTINUATION	$317,785
														Subtotal = $317,785

Issue Date FY: 2011 ( Subtotal = $317,785 )
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	1/20/2011	NON-COMPETING CONTINUATION	$297,923
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	6/9/2011	NON-COMPETING CONTINUATION	$19,862
														Subtotal = $317,785

Issue Date FY: 2010 ( Subtotal = $331,026 )
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	2/19/2010	NON-COMPETING CONTINUATION	$331,026
														Subtotal = $331,026

Issue Date FY: 2009 ( Subtotal = $334,369 )
2009	2009	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	3/16/2009	COMPETING CONTINUATION	$334,369
														Subtotal = $334,369

Issue Date FY: 2005 ( Subtotal = $339,817 )
2005	2005	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	9/8/2005	NON-COMPETING CONTINUATION	$339,817
														Subtotal = $339,817

Issue Date FY: 2004 ( Subtotal = $339,975 )
2004	2004	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/30/2004	NON-COMPETING CONTINUATION	$339,975
														Subtotal = $339,975

Issue Date FY: 2003 ( Subtotal = $340,125 )
2003	2003	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/2/2003	NON-COMPETING CONTINUATION	$340,125
														Subtotal = $340,125

Issue Date FY: 2002 ( Subtotal = $416,727 )
2002	2002	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	3/5/2002	SUPPLEMENT FOR EXPANSION	$76,459
2002	2002	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/22/2002	NON-COMPETING CONTINUATION	$340,268
														Subtotal = $416,727

Issue Date FY: 2001 ( Subtotal = $259,675 )
2001	2001	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/19/2001	NEW	$259,675
														Subtotal = $259,675

Grand Total All Awards = $6,912,127

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Structure-Function Analysis of Sarcospan

Award Number: R01AR048179

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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