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）：蛋白质的聚集与人类疾病密切相关，包括数十种家族性和与年龄相关的疾病，这些疾病共同构成了对我们老龄化人群的主要新兴健康威胁。然而，最近的发现表明蛋白质聚集还可以具有广泛的结构和调节功能。这种非病理性聚集的广度和普遍性在很大程度上尚未被探索。在芽殖酵母（酿酒酵母）中，多种内在无序蛋白（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倾向。转录因子 Mot3 就是这样的一种蛋白质，它是已知的少数能够形成自我繁殖聚集体的蛋白质之一，这些聚集体充当基于蛋白质的遗传元件或朊病毒。通过在聚合状态之间切换，Mot3 拓宽了克隆酵母群体可获得的表型范围。这项工作的目标是 1) 开发 IDP 细胞内聚集的定量流式细胞报告仪，2) 研究聚集对 IDP 调节活动的影响，3) 测试这些蛋白质（尤其是 Mot3）的聚集是否是一种适应性生物过程。这项工作将增进我们对非病理性蛋白质聚集的理解，同时为未来研究活细胞中的功能性和疾病相关聚集建立一个平台。 公共健康相关性：蛋白质的聚集通常对其活性和人类健康有害。然而，蛋白质聚集体也可以具有重要的生物学功能。这项工作将研究芽殖酵母中一大类先前鉴定的易于聚集的蛋白质聚集的生物学后果。在此过程中，它将开发一种强大的新方法来研究活细胞中的功能性和疾病相关的蛋白质聚集。