Investigation into protein quality control pathways in Dictyostelium discoideum

摘要 蛋白质聚集是至少71种疾病的标志。蛋白质聚集体是由 蛋白质动态平衡导致错误折叠的蛋白质堆积。生物医学中的一个主要问题 研究是：细胞如何识别和处理错误折叠的蛋白质？我的实验室用了一种独特的 回答这个问题的方法。而不是研究蛋白质在模型生物中的聚集 容易聚合，我们已经确定盘基网柄菌(Dictyostelium Discoideum)是一个蛋白质组的异常值，高度 抗蛋白质聚集的。利用网柄网柄菌的这一独特特征，我们正在努力识别自然如何 已经解决了蛋白质聚集的问题。一旦我们确定了网柄苔藓利用的机制 抑制蛋白质聚集我们计划确定这种信息是否可以用来开发治疗 战略。在未来五年，我们的目标是对抑制蛋白质的因素进行全面分析 网柄网柄菌内的聚集性。然后，将测试抑制网柄菌体内蛋白质聚集的因素 确定它们是否可以用于治疗由蛋白质聚集引起的人类疾病。除了我们的工作之外 在确定网柄扁藻如何逃避蛋白质聚集方面，我们也感兴趣的是什么生物学作用 抑制蛋白质聚集的途径在网柄蕨类生物学中发挥作用。一个特别感兴趣的领域是 单细胞阿米巴向多细胞子实体过渡的发育周期。这 发育周期之所以令人感兴趣，是因为我们确定的最初的蛋白质抑制因子基因 聚合体是一个大的基因家族的一部分，只在盘基网柄菌和紫盘基网柄菌中发现， 亲缘关系密切的两种经历这种发育过程的生物体。这个基因家族是发育中的 大多数基因在网柄网柄菌期间和之后的时间点短时间内转录的调控 变成多细胞的。在接下来的几年里，我们想要了解这个蛋白质家族在 网柄网柄菌发育研究：蛋白质聚集抑制是否在网柄网柄菌中起关键作用 发展。

Abstract Protein aggregation is a hallmark of at least 71 diseases. Protein aggregates are caused by an imbalance in protein homeostasis resulting in the accumulation of misfolded proteins. One major question in biomedical research is: How do cells recognize and deal with misfolded proteins? My laboratory has taken a unique approach to answering this question. Instead of studying protein aggregation in model organisms where proteins readily aggregate, we have identified Dictyostelium discoideum (Dictyostelium) as a proteostatic outlier, highly resistant to protein aggregation. Using this unique feature of Dictyostelium we are working to identify how nature has dealt with the problem of protein aggregation. Once we determine the mechanisms Dictyostelium utilize to suppress protein aggregation we plan to determine if this information can be used to develop therapeutic strategies. In the next five years our goal is to have a comprehensive analysis of factors that suppress protein aggregation in Dictyostelium. Factors that suppress protein aggregation in Dictyostelium will then be tested to determine if they can be used to treat human diseases caused by protein aggregation. In addition to our work on identifying how Dictyostelium evades protein aggregation we are also interested in what biological role pathways that suppress protein aggregation play in Dictyostelium biology. One particular area of interest is in Dictyostelium’s developmental cycle where single cellular amoeba transition to multicellular fruiting body. This developmental cycle is of interest because the initial gene that we identified as a suppressor of protein aggregation is part of a large gene family found only in Dictyostelium discoideum and Dictyostelium purpureum, two closely related organisms that undergo this developmental process. This gene family is developmentally regulated with most genes being transcribed in short bursts at time points during and after Dictyostelium becomes multicellular. In the coming years we want to understand what role this protein family plays in Dictyostelium development to determine if suppression of protein aggregation plays a critical role in Dictyostelium development.