Contributions of protein aggregation to gene regulation and phenotypic diversity

蛋白质聚集对基因调控和表型多样性的贡献

• 批准号: 8213104
• 负责人: Randal Arthur Halfmann
• 金额: $ 31.7万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213104
• 关键词: Age; Aging; Bacteria; Behavior; Biological; Biological Assay; Biological Process; Biology; Buffers; Cell physiology; Cells; Characteristics; Data; Disease; Elements; Environment; Epigenetic Process; Eukaryota; Future; Gene Expression Regulation; Goals; Growth; Hand; Health; Heterogeneity; Human; Individual; Investigation; Life; Microscopy; Modeling; Molecular; Mutation; Nature; Nutrient; Open Reading Frames; Organism; Phenotype; Physiological; Play; Population; Prions; Process; Protein Kinase; Proteins; RNA-Binding Proteins; Regulation; Reporter; Role; Saccharomyces cerevisiae; Saccharomycetales; Testing; Time; Work; Yeasts; base; biological systems; design; environmental change; genetic regulatory protein; human disease; in vivo; loss of function mutation; mutant; non-prion; novel; novel strategies; prion-like; protein aggregate; protein aggregation; protein expression; protein function; transcription factor

DESCRIPTION (provided by applicant): The aggregation of proteins is deeply associated with human diseases, including dozens of familial and age-associated disorders that together comprise a major emerging health threat to our aging populace. However, recent discoveries indicate that protein aggregation can also have a wide range of structural and regulatory functions. The breadth and pervasiveness of such non-pathological aggregation is largely unexplored. In the budding yeast, Saccharomyces cerevisiae, multiple intrinsically disordered proteins (IDPs), including transcription factors, RNA- binding proteins, and kinases, have a tendency to aggregate under physiological conditions. One such protein, the transcription factor Mot3, is one of only a handful of proteins known to form self-propagating aggregates that act as protein-based elements of inheritance, or prions. By switching to and from its aggregated state, Mot3 broadens the range of phenotypes accessible to clonal yeast populations. The goals of this work are to 1) develop a quantitative flow cytometric reporter for intracellular aggregation by IDPs, 2) investigate the consequences of aggregation on the regulatory activities of IDPs, and 3) test whether aggregation by these proteins, and by Mot3 in particular, is an adaptive biological process. This work will advance our understanding of non-pathological protein aggregation, while establishing a platform for future interrogations of both functional and disease-associated aggregation in living cells. PUBLIC HEALTH RELEVANCE: The aggregation of proteins is generally detrimental to their activities, and to human health. However, protein aggregates can also have important biological functions. This work will investigate the biological consequences of aggregation for a large class of previously identified aggregation-prone proteins in budding yeast. In the process, it will develop a powerful new approach for the interrogation of both functional and disease-associated protein aggregation in living cells.

描述（由申请人提供）：蛋白质的汇总与人类疾病深远有关，包括数十种家族性和年龄相关的疾病，共同构成了对我们衰老的人口衰老的重大健康威胁。但是，最近的发现表明蛋白质聚集也可以具有广泛的结构和调节功能。这种非病理聚集的广度和普遍性在很大程度上没有探索。在萌芽的酵母中，酿酒酵母，多种固有的无序蛋白（IDP），包括转录因子，RNA结合蛋白和激酶，在生理条件下有聚集的趋势。一种这样的蛋白质，即转录因子MOT3，是仅有的少数蛋白质之一，它们已知形成自传播的聚集体，这些蛋白质充当基于蛋白质的遗传元素或prions。通过从其汇总状态切换，MOT3扩大了克隆酵母菌种群可访问的表型的范围。这项工作的目标是1）开发一个定量流式细胞术报告基因，用于通过IDPS进行细胞内聚集，2）研究聚集对IDPS调节活性的后果，3）3）测试这些蛋白质，尤其是MOT3是否是一种适应性生物学过程。这项工作将促进我们对非病理蛋白聚集的理解，同时建立一个平台，以对活细胞中功能和疾病相关的聚集进行未来的询问。 公共卫生相关性：蛋白质的聚集通常不利于其活动和人类健康。但是，蛋白质聚集体也可以具有重要的生物学功能。这项工作将调查大量先前鉴定出的聚集蛋白在发芽的酵母中的聚集的生物学后果。在此过程中，它将开发出一种有力的新方法，用于询问活细胞中功能和疾病相关的蛋白质聚集。