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: 10206543
• 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/10206543
• 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; misfolded protein; 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. 项目总结/文摘