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

基本信息

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
项目类别：
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

项目摘要

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/摘要许多蛋白质除了其天然状态外，还获得折叠引导的替代途径淀粉样蛋白聚集体的形成。淀粉样蛋白生成不仅与以上有关五十种人类疾病也与有益于有机体的功能有关。一旦产生，淀粉样蛋白状态通过天然淀粉样蛋白的掺入和构象转化而得以延续。状态蛋白质、生长复合物的碎片以及在其他物质内部和外部的传输个人。这些中心事件由蛋白质序列和构象、蛋白质质量控制途径和细胞生物学。然而，这些影响因素和过程如何尽管人们越来越认识到交叉对生物体生理学的影响，但人们对它的了解却知之甚少。淀粉样蛋白对从酵母到人类的系统生物学的贡献。目前的这一差距知识是该领域进步的关键障碍，因为我们无法理性地解释、预测、利用和逆转淀粉样蛋白生成及其生理学之间的联系影响。我们的长期目标是通过确定如何平衡这些投入来弥补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朊病毒是一个杰出而稳健的模型。分享很多与后生动物淀粉样蛋白的特征一样，酵母朊病毒是一个自然进化的系统，其中可以在以下条件下访问、研究和遍历分隔表型状态的阈值生理相关条件。我们将利用酵母朊病毒生物学中的二分法，其中相同的事件在不同的背景下会产生不同的结果，作为实验的入口阐明最关键转变的系统平衡：朊病毒的出现、干扰、固化、和毒性。我们的研究将共同阐明蛋白质稳态的分子基础，允许淀粉样蛋白存活或丢失，并将提供一个理解类似淀粉样蛋白的框架高等真核生物中的转变。