Mechanisms Of The Unusual Cytokinesis In Trypanosomes

项目摘要 胞质分裂是细胞分裂的最后阶段，受进化上保守的信号转导调节 从酵母到人类的真核生物中的信号通路。布氏锥虫，一种寄生原生动物 和人类昏睡病的病原体，通过沿着分裂经历独特的胞质分裂模式 纵向细胞轴从新鞭毛子细胞的前端单向向 旧鞭毛子细胞的新生后端。T.布鲁氏菌采用胞质分裂信号通路， 与其人类宿主完全不同;因此，胞质分裂可被用作药物靶点， 这种可怕的人类病原体尽管已经鉴定出了多种 胞质分裂调节剂，这些调节剂之间的功能相互作用和作用顺序仍然很差 明白此外，还不清楚卵裂沟内移是如何启动和调节的， 这些鉴定出的胞质分裂调节因子是否在分裂时与某些细胞骨架蛋白协同作用 犁沟促进犁沟内陷。目前的建议是建立在最近发现的胞质分裂 调节途径，旨在确定已知胞质分裂调节因子之间的功能相互作用， 探讨驱动蛋白在促进胞质分裂起始和进行中的作用机制。在特定 目的1，我们计划进行一个系统的分析之间的功能相互作用的胞质分裂调节 蛋白质在细胞分裂之前和期间。在目标2中，我们计划剖析驱动蛋白-13家族蛋白在细胞中的功能。 调节胞质分裂起始并将该驱动蛋白整合到现有的胞质分裂调节途径中。在 目的3，我们计划研究KLIF相关的细胞骨架蛋白的作用机制，并探索它们在细胞凋亡中的作用。 与KLIF和其他胞质分裂调节因子在驱动卵裂沟内移中的功能相互作用。这些 研究将有助于理解这种不寻常模式的分子机制， T.这些调查的结果可能为 化疗干预

Project Summary Cytokinesis is the final stage of cell division, and is regulated by an evolutionarily conserved signaling pathway in eukaryotic organisms ranging from yeast to humans. Trypanosoma brucei, a parasitic protozoan and causative agent of human sleeping sickness, undergoes a distinct mode of cytokinesis by dividing along the longitudinal cell axes uni-directionally from the anterior end of the new-flagellum daughter cell towards the nascent posterior end of the old-flagellum daughter cell. T. brucei adopts a cytokinesis signaling pathway that is totally different from its human host; therefore, cytokinesis can be exploited as a drug target for combating this dreadful human pathogen. Despite the identification and the functional characterization of multiple cytokinesis regulators, the functional interplay and the order of action among these regulators remain poorly understood. Moreover, it remains also unclear how cleavage furrow ingression is initiated and regulated and whether these identified cytokinesis regulators cooperate with certain cytoskeletal proteins at the cleavage furrow to promote furrow ingression. The current proposal is built on the recently discovered cytokinesis regulatory pathway, and aims to determine the functional interplay among known cytokinesis regulators and to explore the mechanistic roles of kinesin proteins in promoting cytokinesis initiation and progression. In specific Aim 1, we plan to carry out a systematic analysis of the functional interplay among the cytokinesis regulatory proteins before and during cytokinesis. In Aim 2, we plan to dissect the function of a kinesin-13 family protein in regulating cytokinesis initiation and integrate this kinesin into the existing cytokinesis regulatory pathway. In Aim 3, we plan to investigate the mechanistic role of KLIF-associated cytoskeletal proteins and to explore their functional interplay with KLIF and other cytokinesis regulators in driving cleavage furrow ingression. These studies will facilitate the understanding of the molecular mechanism underlying the unusual mode of cytokinesis in T. brucei, and the outcomes from these investigations may provide new targets for chemotherapeutic intervention.