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: 10708140
• 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/10708140
• 关键词: Aging; Alanine; Algorithms; Amyloid; Amyloid Proteins; Amyloid deposition; Archives; Biological Assay; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Aging; Cessation of life; Characteristics; Coupling; Data; Degenerative Disorder; Dependovirus; Deposition; Diagnostic; Disease; 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; 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.

抽象的 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，细胞衰老与 与异常的蛋白相过渡到细胞毒性淀粉样蛋白样聚集体，可能引起器官功能障碍 和退化性疾病。人们已经承认，淀粉样蛋白的心脏沉积会造成损害 心脏，导致心力衰竭的积极形式。因此，迫切需要扩大我们的 对潜在心脏淀粉样蛋白的知识。 Connctophilin-2（JPH2），心脏激发的调节剂 - 收缩耦合和转录是心肌病相关突变的热门目标，包括 与老年患者心脏淀粉样变性的诊断表型相关的突变。我们的出版物 第一次发现JPH2具有形成淀粉样蛋白样聚集体的内在能力。我们已经确定了 突变和可能诱导JPH2聚集的翻译后修饰。重要的是，我们 在小鼠心脏中检测到的JPH2依赖年龄依赖性的相位过渡到SDS不溶性状态。基于这些 初步数据，我们假设心肌细胞中类似淀粉样蛋白的JPH2聚集可以通过衰老或 突变，并导致心脏功能障碍。该提案特别针对1。 表征JPH2聚集体的淀粉样蛋白性质； 2。定义JPH2聚合的总体后果 心脏功能； 3。确定几种人类心肌病与JPH2突变的影响 该蛋白的淀粉样蛋白样相变。该提议很重要，因为定义年龄依赖性 JPH2的异常相转变将为衰老提供新的机制和潜在的治疗靶标 相关心脏功能障碍。 JPH2通常被认为对心脏有益，并且过表达 该蛋白被认为是一种治疗策略。这项研究将揭示该蛋白质的病理作用 作为细胞内淀粉样蛋白的来源，并评估了衰老心脏中过表达JPH2的潜在隐藏风险。 该建议是新颖的，因为它提供了定义新型心脏淀粉样蛋白涉及的机会 在衰老相关的心脏病理学中。我们预计通过 拟议的研究将使我们能够竞争长期资金，以系统地探索病理 衰老心脏中JPH2淀粉样相变的意义和机制。