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

Junctophilin-2 蛋白在心脏衰老过程中的类淀粉样相变

• 批准号: 10593215
• 负责人: Ang Guo
• 金额: $ 7.25万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593215
• 关键词: Aging; Alanine; Amyloid; Amyloid Proteins; Amyloid deposition; Archives; Biological Assay; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Aging; Cessation of life; Characteristics; Consequentialism; Coupling; Data; Degenerative Disorder; Dependovirus; Deposition; Diagnostic; Disease; Elderly; Fluorescence Recovery After Photobleaching; Functional disorder; Funding; Genetic Transcription; Growth; Heart; Heart failure; Hot Spot; Human; In Vitro; Interruption; Knowledge; Liquid substance; Long-Term Effects; Mediating; Methods; Missense Mutation; Modeling; Modification; Molecular; Mus; Mutation; Myocardial dysfunction; Myocardium; Nature; Organ; Pathologic; Pathology; Patients; Phase; Phase Transition; Phenotype; Physiological; Post-Translational Protein Processing; Protein Overexpression; Proteins; Publications; Reporting; Research; Risk; Role; Solubility; Source; Stains; Therapeutic; Time; Transmission Electron Microscopy; United States; age related; aged; alpha helix; base; beta pleated sheet; cardiac amyloidosis; cell injury; cytotoxic; extracellular; gene therapy; heart function; human old age (65+); interdisciplinary approach; junctophilin; misfolded protein; mutant; novel; older patient; overexpression; prevent; protein aggregation; therapeutic target; three dimensional structure; tool

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.

摘要