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Amyloid-like phase transition of Junctophilin-2 protein in heart aging

Award Number: R03AG077141
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Amyloid-like phase transition of Junctophilin-2 protein in heart aging - Abstract Over 90% of heart failure deaths occur in patients over the age of 65. In many cases, cell aging is associated with aberrant protein phase transition to cytotoxic amyloid-like aggregates, which can cause organ dysfunction and degenerative diseases. It has been acknowledged that cardiac deposition of amyloids can cause damage to the heart and result in an aggressive form of heart failure. Therefore, there is a great need to expand our knowledge of potential cardiac amyloidogenic proteins. Junctophilin-2 (JPH2), a regulator of cardiac excitation- contraction coupling and transcription, is a hot target for cardiomyopathy associated mutations, including a mutation associated with diagnostic phenotypes of cardiac amyloidosis in aged patient. Our publication for the first time discovered that JPH2 has an intrinsic capability to form amyloid-like aggregates. We have identified mutations and possible posttranslational modifications that induce the aggregation of JPH2. Importantly, we detected age-dependent phase transition of JPH2 into SDS insoluble state in mouse hearts. Based on these preliminary data, we hypothesize amyloid-like JPH2 aggregation in cardiomyocytes can be induced by aging or mutations, and consequentially contribute to cardiac dysfunction. This proposal specifically aims at 1. characterize the amyloid nature of JPH2 aggregates; 2. defining the overall consequences of JPH2 aggregation for cardiac function; 3. determining the effect of several human cardiomyopathy associated JPH2 mutations on amyloid-like phase transition of this protein. This proposal is significant because defining the age-dependent aberrant phase transition of JPH2 would provide new mechanisms and potential therapeutic targets for the aging related heart dysfunction. JPH2 is conventionally considered to be beneficial for heart, and overexpression of this protein is considered to be a therapeutic strategy. This study would reveal a pathological role of this protein as a source of intracellular amyloids, and evaluate a potential hidden risk of overexpressing JPH2 in aging hearts. This proposal is novel, because it offers an opportunity to define a novel cardiac amyloidogenic protein involved in aging related cardiac pathology. We anticipate that the molecular tools, methods, and data generated through the proposed studies will enable us to compete for long-term funding to systematically explore the pathological significance and mechanisms of JPH2 amyloid phase transition in aging hearts.


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 = $0 )
2025	2023	NORTH DAKOTA STATE UNIVERSITY	1301 12TH AVE N	FARGO	ND	58102	CASS	USA	Aging Research	000	2	10/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $72,500 )
2023	2023	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Aging Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	$72,500
														Subtotal = $72,500

Issue Date FY: 2022 ( Subtotal = $72,500 )
2022	2022	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Aging Research	000	1	9/21/2022	NEW	$72,500
														Subtotal = $72,500

Grand Total All Awards = $145,000

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Amyloid-like phase transition of Junctophilin-2 protein in heart aging

Award Number: R03AG077141

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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