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Genetics and Molecular Biology of Striated Muscle Myosin

Award Number: R37GM032443
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1983
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Genetics and Molecular Biology of Striated Muscle Myosin - We are probing the role of the myosin motor in aging and in progressive, genetically based diseases of skeletal and cardiac muscles using transgenic models of Drosophila melanogaster. We take advantage of the powerful genetic tools available for Drosophila to study myosin in an integrative manner, from atomic structural details and biochemical function through muscle ultrastructure, fiber mechanics, cardiac physiology and locomotion. We are examining the functional significance of specific residues within the skeletal muscle myosin motor and rod domains that are post-translationally modified during human aging. These modifications cause indirect flight muscle atrophy and dysfunction in our transgenic lines. To understand the basis of these defects, we are assessing myosin ATPase activity, in vitro motility, thick filament formation and fiber mechanics. We will determine if aging-related accumulation of ubiquinated protein aggregates and inclusion bodies is augmented in these lines, and will examine whether expression of the autophagy- enhancer FOXO ameliorates such disrupted proteostasis. Secondly, we will define the roles of proteins that anomalously accumulate in aggregates in our Drosophila models of inclusion body myopathy type 3 and myosin storage myopathy. Both are progressive skeletal muscle disorders that we found to exhibit aberrant proteostasis, yet they display phenotypically different protein aggregates. We will examine the structural and functional defects in skeletal muscles that arise from up- or down-regulating expression of the aberrant aggregate proteins as well as the effects of over-expressing FOXO. This will yield insights into roles of these proteins in aging and in degenerative muscle diseases. Finally, we are examining how mutations associated with human age-exacerbated dilated cardiomyopathy affect the structure and function of the Drosophila heart. We will determine mutation effects on cardiac proteostasis and examine if FOXO ameliorates mutation effects. Using a unique in vivo method to produce mutant myosins, we will gain mechanistic insights into biochemical and structural defects through ATPase and in vitro motility assays and by solving cardiac protein structures via crystallography. Further, we will express these mutant cardiac myosins in skeletal muscles to understand functional effects on muscle contractile properties. Overall, our project will test significant questions regarding basic myosin function during aging of healthy and diseased skeletal and cardiac muscles and assess whether improving proteostasis aids in rectifying muscle degeneration.


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 = $548,562 )
2025	2025	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	40	4/30/2025	NON-COMPETING CONTINUATION	$548,562
														Subtotal = $548,562

Issue Date FY: 2024 ( Subtotal = $567,091 )
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	002	39	6/21/2024	NON-COMPETING CONTINUATION	$54,119
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	39	4/17/2024	NON-COMPETING CONTINUATION	$487,076
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	39	4/18/2024	SUPPLEMENT FOR EXPANSION	$25,896
														Subtotal = $567,091

Issue Date FY: 2023 ( Subtotal = $654,172 )
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	005	38	9/7/2023	SUPPLEMENT FOR EXPANSION	$35,289
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	004	38	5/4/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	002	38	4/27/2023	NON-COMPETING CONTINUATION	$541,195
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	003	38	4/28/2023	SUPPLEMENT FOR EXPANSION	$77,688
2023	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	37	10/25/2022	EXTENSION WITH OR WITHOUT FUNDS	$79,922
2023	2021	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	36	10/25/2022	NON-COMPETING CONTINUATION	-$79,922
														Subtotal = $654,172

Issue Date FY: 2022 ( Subtotal = $655,394 )
2022	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	37	3/31/2022	EXTENSION WITH OR WITHOUT FUNDS	$603,601
2022	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	37	9/6/2022	SUPPLEMENT FOR EXPANSION	$51,793
														Subtotal = $655,394

Issue Date FY: 2021 ( Subtotal = $515,469 )
2021	2021	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	36	4/16/2021	NON-COMPETING CONTINUATION	$515,469
														Subtotal = $515,469

Issue Date FY: 2020 ( Subtotal = $515,469 )
2020	2020	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	35	3/31/2020	NON-COMPETING CONTINUATION	$515,469
														Subtotal = $515,469

Issue Date FY: 2019 ( Subtotal = $515,469 )
2019	2019	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	34	4/26/2019	NON-COMPETING CONTINUATION	$515,469
														Subtotal = $515,469

Issue Date FY: 2018 ( Subtotal = $572,191 )
2018	2018	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	33	4/26/2018	NON-COMPETING CONTINUATION	$540,693
2018	2017	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	32	12/2/2017	COMPETING CONTINUATION	$31,498
														Subtotal = $572,191

Issue Date FY: 2017 ( Subtotal = $401,788 )
2017	2017	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	32	6/7/2017	COMPETING CONTINUATION	$401,788
														Subtotal = $401,788

Grand Total All Awards = $4,945,605

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Genetics and Molecular Biology of Striated Muscle Myosin

Award Number: R37GM032443

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1983

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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