Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

蛋白质错误折叠和解析的细胞机制和后果

• 批准号: 10470161
• 负责人: TRICIA R. SERIO
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470161
• 关键词: Amino Acid Sequence; Amyloid; Appearance; Biology; Cellular biology; Characteristics; Complex; Disease; Equilibrium; Eukaryota; Event; Goals; Individual; Knowledge; Link; Modeling; Molecular; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Organism; Outcome; Pathway interactions; Phenotype; Physiological; Physiology; Prions; Process; Protein Conformation; Proteins; Quality Control; Resolution; Saccharomyces cerevisiae; System; Systems Biology; Toxic effect; Yeasts; amyloid formation; amyloidogenesis; conformational conversion; familial hypertension; human disease; man; protein misfolding; transmission process; yeast prion

8. Project Summary/Abstract Many proteins access, in addition to their native state, an alternative pathway of folding leading to the formation of amyloid aggregates. Amyloidogenesis has been linked not only to more than fifty human diseases but also to functions, which benefit the organism. Once arising, the amyloid state is perpetuated through the incorporation and conformational conversion of native- state protein, fragmentation of growing complexes and transmission both within and to other individuals. These central events are modulated by protein sequence and conformation, protein quality control pathways, and cell biology. Yet, how these contributing factors and processes intersect to impact organismal physiology is poorly understood, despite a growing appreciation of the contributions of amyloid to the biology of systems from yeast to man. This current gap in knowledge is a critical barrier to progress in the field because we are unable to rationally explain, predict, exploit, and reverse the link between amyloidogenesis and its physiological effects. Our long-term goal is to bridge this gap by determining how these inputs are balanced and disrupted to create and cure dynamic phenotypic states. Toward this end, we are exploiting prions of Saccharomyces cerevisiae as an outstanding and robust model. Sharing many characteristics with metazoan amyloids, yeast prions are a naturally evolved system in which the thresholds separating phenotypic states can be accessed, studied, and traversed under physiologically relevant conditions. We will exploit dichotomies in yeast prion biology, where the same event yields distinct outcomes in different contexts, as experimental entryways to elucidate system balance for the most crucial transitions: prion appearance, interference, curing, and toxicity. Together, our studies will elucidate the molecular basis of proteostatic niches that allow amyloid to survive or to be lost and will provide a framework for understanding similar transitions in higher eukaryotes.

8。项目摘要/摘要 除本地状态外，许多蛋白质访问是折叠领先的另一种途径 淀粉样蛋白聚集体的形成。淀粉样生成不仅与 五十种人类疾病，但也从事有机体的功能。一旦出现， 淀粉样蛋白状态通过天然的结合和构象转化而永久存在 状态蛋白质，在内部和其他内部和其他 个人。这些中心事件由蛋白质序列和构象调节，蛋白质 质量控制途径和细胞生物学。但是，这些贡献因素和过程如何 尽管人们越来越欣赏 淀粉样蛋白对从酵母到人的系统生物学的贡献。当前的差距 知识是该领域进步的关键障碍，因为我们无法合理地 解释，预测，利用和扭转淀粉样生成与其生理学之间的联系 效果。我们的长期目标是通过确定这些投入如何平衡来弥合这一差距 并破坏以创建和治愈动态表型状态。为此，我们正在利用 酿酒酵母的葡萄酒是一种杰出而强大的模型。分享许多 酵母菌王室的特征是一种自然发展的系统 可以在下面访问，研究和穿越的分离表型状态的阈值 生理上相关的条件。我们将利用酵母菌生物学的二分法 在不同情况下，同一事件在不同的情况下产生不同的结果 阐明最关键过渡的系统平衡：prion外观，干扰，固化， 和毒性。总之，我们的研究将阐明蛋白抑制壁ches的分子基础 允许淀粉样蛋白生存或丢失，并将提供一个理解类似的框架 高等真核生物的过渡。