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Treating Hyperkalemic Periodic Paralysis

Award Number: F30AR081675
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Treating Hyperkalemic Periodic Paralysis - Project Summary/Abstract Hyperkalemic Periodic Paralysis (HyperKPP) is one of a family of inherited skeletal muscle diseases known as the ion channelopathies. HyperKPP patients have mutations in the skeletal muscle Nav1.4 sodium channel. Importantly, patients suffer intermittent attacks of muscle paralysis and weakness lasting from minutes to days. Despite identification of the gene responsible, mechanisms underlying the attacks of weakness remain poorly understood, and current therapies are only modestly effective and have side effects. A mouse model of HyperKPP has been generated, which recapitulates the key aspects of the disorder in patients. The mouse model will be used to identify mechanisms contributing to failure of excitation contraction coupling caused by pathologic depolarization of the membrane potential. These correlated studies will range from ex vivo whole- muscle force recordings down to measurement of Ca transients in single fibers. A new technique allows for simultaneous, intracellular recordings of action potentials and Ca transients of single muscle fibers in an intact muscle. The overall goal is to address currently poorly understood aspects of HyperKPP and to develop novel strategies for better therapies. This will be done in three Specific Aims: 1) Determine the mechanisms underlying depolarization-induced failure of excitation contraction coupling (ECC) in normal muscle: Pilot data suggests failure of ECC is more complex than previously suspected. The proposed correlated studies will elucidate the events preceding failure of ECC. 2) Determine the extent to which depolarization of the membrane potential contributes to failure of ECC in HyperPP. The proposed studies will determine whether excessive depolarization of mutant muscle can fully account for weakness. A series of electrophysiology experiments in HyperKPP vs. wild-type mice will address this fundamental question. 3) Examine block of depolarizing current with a more selective blocker as an effective therapy for HyperKPP. If the primary cause of HyperKPP is muscle depolarization, blocking the depolarizing current should provide effective therapy. However, clinical studies suggest that the current Na channel blockers are not effective in patients. Identification of mechanisms contributing to depolarization-induced weakness in HyperKPP has implications for all diseases in which depolarization of muscle contributes to weakness. If effective therapies are found to treat weakness in the mouse model of HyperkPP, future work will be directed at translating findings to clinical trials in patients.


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 = $54,538 )
2025	2025	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	9/12/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/7/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $45,077 )
2023	2023	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/11/2023	NON-COMPETING CONTINUATION	$45,077
														Subtotal = $45,077

Issue Date FY: 2022 ( Subtotal = $44,135 )
2022	2022	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/1/2022	NEW	$44,135
														Subtotal = $44,135

Grand Total All Awards = $197,724

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Treating Hyperkalemic Periodic Paralysis

Award Number: F30AR081675

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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