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

基本信息

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
项目类别：
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

项目摘要

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，细胞衰老与异常蛋白质相转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。众所周知，淀粉样蛋白沉积在心脏会造成损害影响心脏并导致侵袭性心力衰竭。因此，非常有必要扩大我们的了解潜在的心脏淀粉样蛋白。 Junctophilin-2 (JPH2)，心脏兴奋的调节剂 - 收缩耦合和转录是心肌病相关突变的热门靶标，包括与老年患者心脏淀粉样变性诊断表型相关的突变。我们的出版物首次发现JPH2具有形成淀粉样蛋白聚集体的内在能力。我们已经确定诱导 JPH2 聚集的突变和可能的翻译后修饰。重要的是，我们检测到 JPH2 在小鼠心脏中向 SDS 不溶状态的年龄依赖性相变。基于这些根据初步数据，我们假设心肌细胞中淀粉样蛋白样 JPH2 聚集可以由衰老或衰老引起突变，从而导致心脏功能障碍。该提案具体针对 1. 表征 JPH2 聚集体的淀粉样蛋白性质； 2. 定义 JPH2 聚合的总体后果对于心脏功能； 3. 确定几种人类心肌病相关的 JPH2 突变对该蛋白质的淀粉样蛋白相变。该提案意义重大，因为定义了与年龄相关的 JPH2的异常相变将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。 JPH2 传统上被认为对心脏有益，而 JPH2 的过度表达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，并评估衰老心脏中过度表达 JPH2 的潜在隐藏风险。这个提议是新颖的，因为它提供了一个机会来定义涉及的新型心脏淀粉样蛋白与衰老相关的心脏病理学。我们预计通过生成的分子工具、方法和数据拟议的研究将使我们能够竞争长期资金，以系统地探索病理学 JPH2 淀粉样蛋白相变在衰老心脏中的意义和机制。