Monday, June 30, 2025 6/30/2025

cryoEM Studies of Muscle

Award Number: R35GM139616
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: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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cryoEM Studies of Muscle - Project Summary The long term goal of this research project has been and continues to be an understanding of the molecular mechanism of muscle function. The existing project, funded continuously since 1983, has evolved in parallel with the capabilities of both microscopes and methods for 3-D image reconstruction from electron microscopes. Originally focused on understanding myosin-actin interactions in situ in muscle using chemically fixed, plastic embedded and sectioned muscle, it now proposes to take advantage of the resolution revolution in cryoEM to study the major structural elements of the muscle at the highest resolution possible using isolated components, followed by a return to imaging actin-myosin interactions in situ in frozen live muscle cells. Striated muscles have four major components: actin-containing thin filaments, myosin- containing thick filaments, a Z-disk to crosslink antiparallel thin filaments and a connecting filament to link the thick filaments to the Z-disk. The least understood of these four elements are the thick filament, the Z-disk and the connecting filament, whose interactions with the thick filament and Z-disk are its least understood elements. Thus, our study of Z-disk and thick filament can make major contributions to an understanding of all three elements. Following a major breakthrough of ours that showed that coiled-coil tail domain of myosin can be imaged at subnanometer resolution, even near atomic resolution, the project concentrates initially on subnanometer resolution imaging of thick filaments from several species, to examine the generality and structural conservation of the “curved molecular crystalline layers” across species and muscle types. The project will utilize the fruit fly, Drosophila melanogaster, to investigate how genetic removal of certain component proteins affects how the myosin tails interact with non-myosin proteins to affect thick filament properties. We will utilize mutations in the myosin tail of Drosophila that correspond to established disease causing mutations in human striated muscle. The Z-disk will be studied using methodology developed in our lab to isolate Z-disks from invertebrates applied to determination of the Drosophila melanogaster Z-disk. The experimental system will facilitate decoration of the Z-disks with various signaling proteins. Ultimately, the utility of these studies on components needs development within the myofibril. We will investigate by cryoelectron tomography frozen-hydrated myofibrils of Lethocerus and Drosophila thinned using FIB/SEM in states produced using various nucleotides to see how myosin heads interact with the thin filament in situ. Ultimately, we will apply what we have learned methodologically from these myofibril studies to studies of live cultured smooth and cardiac muscle cells fast frozen, thinned via FIB/SEM to visualize active interactions between thick and thin filaments. This work will open to future structural investigation all the structures present in a muscle cell within their natural context.


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 = $397,633 )
2025	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	5	1/15/2025	NON-COMPETING CONTINUATION	$397,633
2025	2024	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $397,633

Issue Date FY: 2024 ( Subtotal = $441,815 )
2024	2024	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	4	6/20/2024	NON-COMPETING CONTINUATION	$44,182
2024	2024	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	12/19/2023	NON-COMPETING CONTINUATION	$397,633
														Subtotal = $441,815

Issue Date FY: 2023 ( Subtotal = $441,815 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	3	12/19/2022	NON-COMPETING CONTINUATION	$397,633
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	3	2/27/2023	NON-COMPETING CONTINUATION	$44,182
														Subtotal = $441,815

Issue Date FY: 2022 ( Subtotal = $441,815 )
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	2	1/14/2022	NON-COMPETING CONTINUATION	$397,633
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	2	6/27/2022	NON-COMPETING CONTINUATION	$44,182
														Subtotal = $441,815

Issue Date FY: 2021 ( Subtotal = $614,948 )
2021	2021	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	1	12/23/2020	NEW	$365,348
2021	2021	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	1	8/27/2021	SUPPLEMENT FOR EXPANSION	$249,600
														Subtotal = $614,948

Grand Total All Awards = $2,338,026

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cryoEM Studies of Muscle

Award Number: R35GM139616

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: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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