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Mechanisms Of The Unusual Cytokinesis In Trypanosomes

锥虫异常细胞分裂的机制

基本信息

批准号：
10581682
负责人：
Ziyin Li
金额：
$ 54.24万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-06 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581682
关键词：
Actomyosin Address Adopted African Trypanosomiasis Anterior Automobile Driving Biochemical Biological Cell division Cells Cytokinesis Cytoskeletal Proteins Cytoskeleton Disease Drug Targeting Evolution Foundations Genetic Goals Human Investigation Kinesin Mediating Microtubules Molecular Names Organism Orphan Outcome PLK1 gene Parasites Parasitic Diseases Pathway interactions Pharmaceutical Preparations Physiological Protein Family Protein Kinase Proteins Regulation Regulatory Pathway Research Role Signal Pathway Signal Transduction Site Testing Therapeutic Intervention Trypanosoma Trypanosoma brucei brucei Yeasts aurora B kinase cohort daughter cell drug development genetic approach genetic regulatory protein human pathogen insight new therapeutic target novel protein protein interaction public health relevance screening spatiotemporal vector-borne

项目摘要

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.

项目摘要胞质分裂是细胞分裂的最后阶段，由进化上保守的信号调节。真核生物中的途径，从酵母到人类。布鲁氏锥虫--一种寄生原虫和人类昏睡病的病原体，经历了一种独特的细胞质分裂模式纵向细胞轴从新鞭毛子细胞的前端单向地朝向旧鞭毛子细胞的新生后端。布氏锥虫采用胞质分裂信号通路，与人类宿主完全不同；因此，胞质分裂可以被用作对抗这种可怕的人类病原体。尽管鉴定和功能表征了多个胞质分裂调节因子、这些调节因子之间的功能相互作用和作用顺序仍然很差。明白了。此外，还不清楚乳沟侵入是如何启动和调节的，以及这些已识别的胞质分裂调节因子是否与某些细胞骨架蛋白在卵裂处协同作用以沟促沟进。目前的建议是建立在最近发现的细胞质分裂的基础上的调控途径，旨在确定已知的细胞质分裂调节因子之间的功能相互作用，并探索动蛋白在促进胞质分裂启动和进展中的机制作用。具体而言目的1，我们计划对胞质分裂调节之间的功能相互作用进行系统的分析胞质分裂前和胞质分裂期间的蛋白质。在目标2中，我们计划剖析一个Kinesin-13家族蛋白的功能。调节胞质分裂的启动，并将该激动素整合到现有的胞质分裂调节途径中。在……里面目的3，我们计划研究KLIF相关细胞骨架蛋白的作用机制，并探讨其机制。与KLIF和其他细胞质分裂调节因子的功能相互作用驱动卵裂沟内移。这些研究将有助于理解这一异常模式背后的分子机制。布氏毛滴虫的胞质分裂，这些研究结果可能为化疗干预。