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

基本信息

批准号：
8335441
负责人：
Randal Arthur Halfmann
金额：
$ 31.8万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8335441
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

项目摘要

ABSTRACT 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.

抽象的蛋白质的聚集与人类疾病有着密切相关的，包括数十种家族性和与年龄相关的疾病共同构成了重大新兴的健康威胁我们老化的人民。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。的广度和普遍性这种非病理聚集在很大程度上没有探索。在萌芽的酵母中酿酒酵母，多种本质上无序的蛋白质（IDP），包括转录因子，RNA- 结合蛋白和激酶具有在生理条件下聚集的趋势。一种这样的蛋白质，即转录因子MOT3，是仅有的少数已知蛋白质之一形成自传播的聚集体，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扩大了表型的范围克隆酵母菌种群可以使用。这项工作的目标是1）制定定量流式细胞仪记录器用于IDP的细胞内聚集，2）研究后果在IDP的监管活动中的汇总，以及3）测试是否汇总蛋白质，尤其是MOT3是一种自适应生物学过程。这项工作将推动我们的了解非病理蛋白质聚集，同时建立未来平台对活细胞中功能和疾病相关的聚集的询问。