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Caspase-mediated nuclear pore complex trimming in myogenesis and muscular dystrophies

Award Number: K01AR080828
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Caspase-mediated nuclear pore complex trimming in myogenesis and muscular dystrophies - PROJECT SUMMARY/ABSTRACT Caspases are a group of proteases most well known for their destructive role in apoptosis. While their activation is often equated with cell death, in skeletal muscles, this does not hold true. For example, during myogenic differentiation, caspases are activated in a transient, regulated, and reversible manner. These proteases can also be activated chronically in Duchenne or limb-girdle muscular dystrophies. Nevertheless, very little is known about the non-apoptotic roles of caspases in muscle formation and degeneration. By focusing on caspase-mediated trimming of the nuclear pore complex (NPC), this K01 project will elucidate how sublethal caspases bring about such contrasting outcomes. Caspases can proteolyze four distal subunits of the NPC, impair nuclear export, and entrap several NES (nuclear export signal)-containing proteins, many of which have genome regulatory functions. In Aim 1, NES-containing proteins that accumulate in the nucleus during myogenesis and drive genome reconfiguration will be identified in an unbiased manner. In addition, a focused study will be conducted to understand how FAK, an NES-containing focal adhesion protein that doubles as a transcription cofactor in the nucleus, interacts with MBD2, a methyl CpG-binding protein, to de-repress myogenic genes. In Aim 2, caspase-mediated NPC trimming in dystrophic muscles will be assessed. Given that modest activation of caspases by ER stressors is sufficient to cause NPC trimming and nuclear export shutdown in myotubes, the NPC in dystrophic muscles will be similarly modified and dysfunctional. Therefore, a proteome- wide search will be performed to identify proteins whose nuclear levels are abnormally high in dystrophic myonuclei and have potential to induce genome dysregulation. In short, by dissecting the antagonistic pleiotropy of the caspase-NPC-nuclear export axis, this proposal aims to provide a foundation for new therapeutic approaches that promote muscular health in both healthy individuals and muscular dystrophy patients. This research combines the expertise of the Martin Hetzer lab (the Salk Institute) in the NPC and that of the Lorenzo Puri lab (Sanford-Burnham-Prebys) in muscle biology. Dr. Cho’s long-term goal is to lead a research group that studies nuclear proteome and proteases in the context of myogenesis and muscular dystrophies. K01 award will provide him the stability, networking opportunity, and confidence to develop into a young leader in the field of muscle biology who is proficient in both reductionist and systems approaches.


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 = $125,683 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/4/2024	NON-COMPETING CONTINUATION	$125,683
														Subtotal = $125,683

Issue Date FY: 2024 ( Subtotal = $117,109 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/29/2023	NON-COMPETING CONTINUATION	$125,685
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	2/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$111,818
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/15/2024	NON-COMPETING CONTINUATION	-$122,908
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	2	9/6/2024	NON-COMPETING CONTINUATION	$0
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	2	2/23/2024	NON-COMPETING CONTINUATION	$2,514
														Subtotal = $117,109

Issue Date FY: 2023 ( Subtotal = $125,685 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/31/2023	NEW	$125,685
														Subtotal = $125,685

Grand Total All Awards = $368,477

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Caspase-mediated nuclear pore complex trimming in myogenesis and muscular dystrophies

Award Number: K01AR080828

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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