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 超过90%的心力衰竭死亡发生在65岁以上的患者中。在许多情况下，细胞老化与 异常蛋白质相变为细胞毒性淀粉样蛋白聚集体，可导致器官功能障碍 和退行性疾病。已经认识到，淀粉样蛋白的心脏沉积可引起损害 导致严重的心力衰竭因此，非常需要扩大我们的 潜在的心脏淀粉样蛋白的知识。嗜连接蛋白-2（JPH 2）是心脏兴奋的调节因子， 收缩偶联和转录，是心肌病相关突变的热门靶点，包括心肌病相关突变。 老年人心脏淀粉样变性诊断表型相关突变我们的出版物 首次发现JPH 2具有形成淀粉样聚集体的内在能力。我们已经确定 突变和可能的翻译后修饰，诱导JPH 2的聚集。重要的是我们 在小鼠心脏中检测到JPH 2向SDS不溶性状态的年龄依赖性相变。基于这些 初步数据，我们假设心肌细胞中淀粉样蛋白样JPH 2聚集可以由衰老或 突变，并因此导致心脏功能障碍。该提案的具体目标是1. 表征JPH 2聚集体的淀粉样蛋白性质; 2.定义JPH 2聚合的总体后果 心脏功能; 3.确定几种人类心肌病相关JPH 2突变对 这种蛋白质的淀粉样相变。这一建议意义重大，因为定义年龄依赖性 JPH 2的异常相变可能为衰老提供新的机制和潜在的治疗靶点 相关的心脏功能障碍。JPH 2通常被认为对心脏有益，并且JPH 2的过表达被认为对心脏有益。 这种蛋白质被认为是一种治疗策略。这项研究将揭示这种蛋白质的病理作用 作为细胞内淀粉样蛋白的来源，并评估在衰老心脏中过度表达JPH 2的潜在隐藏风险。 这个建议是新颖的，因为它提供了一个机会，以确定一个新的心脏淀粉样蛋白参与， 与衰老有关的心脏病理学我们预计，分子工具，方法和数据产生的，通过 建议的研究将使我们能够争取长期的资金，以系统地探讨病理学 JPH 2淀粉样蛋白在衰老心脏中相变的意义和机制