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Altered nucleus-cytoskeleton coupling in dystrophic muscle

Award Number: K01AR074048
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/20/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Altered nucleus-cytoskeleton coupling in dystrophic muscle - Project Summary: Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy, is characterized by progressive wasting of skeletal muscles and marked susceptibility to damage. Several associated processes could underlie the pathology. The nucleus, a regulator of gene expression and a mechanotransduction hub, has increased movement in mdx (murine model of DMD) muscle. Microtubules (MTs) serve as the “railroad tracks” for cellular organelle transport, including the nucleus. The nucleus is connected to MTs and the rest of the cytoskeleton through the LINC (linkers of nucleus and cytoskeleton) complex. Both, MT organization and LINC complex expression are altered in dystrophic muscle. I will test the hypothesis that nuclear instability, due to disease-driven MT network and LINC complex alterations, results in improper myonuclear domain maintenance (with hypermobile and improperly positioned nuclei), and impaired nuclear mechanotransduction, further driving muscle weakness and susceptibility to injury in dystrophic muscle. In WT and mdx muscle I will measure: 1) nuclear spatial distribution & nuclear movement using time-lapse microscopy 2) myonuclear domain maintenance by measuring RNA spatial distribution of cargoed proteins using fluorescence in-situ hybridization; and nuclear movement & global transcriptional activity following gaps in myonuclear domain using laser ablation 3) nuclear localization of Yes- associated protein (a nuclear relay of mechanical signaling), ERK 1/2 (a key marker of muscle growth) and FRET based nuclear strain sensors, as end points of nuclear mechanotransduction, following passive stretch, isometric and eccentric contractions 4) myonuclear domain maintenance and nuclear mechanotransduction, following blockage of stretch activated channels to block sarcolemmal signaling pathways 5) the above parameters using established genetic/pharmacologic manipulations to the MT network & the LINC complex, and following mini- and micro-dystrophins that have previously shown to either fully or partially rescue MT network and susceptibility to injury Successful completion of this proposal will allow for the development of new avenues to improve musculoskeletal health for patients with DMD, and potentially other dystrophies. This proposal takes place in a multi-disciplinary environment at University of Maryland School of Medicine, with support from experts in physical therapy, physiology, molecular biology, biochemistry, and engineering, such that I can gain skills in cellular and muscle mechanics to move towards an independent, tenure-track research faculty position.


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 = $83,271 )
2023	2023	MARYMOUNT UNIVERSITY	2807 N GLEBE RD	ARLINGTON	VA	22207	ARLINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	3/17/2023	NON-COMPETING CONTINUATION	$83,271
2023	2022	MARYMOUNT UNIVERSITY	2807 N GLEBE RD	ARLINGTON	VA	22207	ARLINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	1/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$64,796
2023	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/19/2023	NON-COMPETING CONTINUATION	-$64,796
2023	2022	MARYMOUNT UNIVERSITY	2807 N GLEBE RD	ARLINGTON	VA	22207	ARLINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	5	5/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,656
2023	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	4	5/26/2023	NON-COMPETING CONTINUATION	-$2,656
														Subtotal = $83,271

Issue Date FY: 2022 ( Subtotal = $84,104 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/28/2022	NON-COMPETING CONTINUATION	$84,104
														Subtotal = $84,104

Issue Date FY: 2021 ( Subtotal = $84,104 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/5/2021	NON-COMPETING CONTINUATION	$84,104
														Subtotal = $84,104

Issue Date FY: 2020 ( Subtotal = $84,104 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/10/2020	NON-COMPETING CONTINUATION	$84,104
														Subtotal = $84,104

Issue Date FY: 2019 ( Subtotal = $84,104 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/3/2019	NEW	$84,104
														Subtotal = $84,104

Grand Total All Awards = $419,687

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Altered nucleus-cytoskeleton coupling in dystrophic muscle

Award Number: K01AR074048

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/20/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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