The role of polo-like kinase in the duplication of the trypanosome cytoskeleton

Polo 样激酶在锥虫细胞骨架复制中的作用

• 批准号: 8886203
• 负责人: Christopher Luis de Graffenried
• 金额: $ 40.12万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886203
• 关键词: Acute; Adherence; Affect; African Trypanosomiasis; Binding; Biochemical; Biotinylation; Cattle; Cell Cycle; Cell Line; Cell Polarity; Cell division; Cells; Cellular Morphology; Complement; Complex; Cytoskeleton; Data Analyses; Defect; Drug Design; Drug Targeting; Eukaryota; Event; Flagella; Future; Goals; Homologous Gene; Human; Immune; Immune Sera; In Vitro; Intervention; Investigation; Knock-out; Location; Mammals; Methods; Molecular; Morphogenesis; Morphology; Mutation; Organelles; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenocopy; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Process; Proteins; Proteomics; RNA Interference; Recruitment Activity; Resistance; Role; Series; Site; Surface; Time; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis; Work; analog; base; cell motility; drug candidate; drug discovery; effective therapy; human PLK1 protein; in vivo; nagana; novel; pathogen; protein function; public health relevance; research study

 DESCRIPTION (provided by applicant): Trypanosoma brucei is the causative agent of African trypanosomiasis in humans and nagana in cattle. The few effective treatments available for treating trypanosomiasis are very difficult to administer and resistance is an emerging problem. Few new drugs are under investigation, which makes identifying novel treatments for this pathogen an urgent need. Trypanosomes are highly polarized and have a complex cytoskeleton that positions the parasite's single flagellum in the posterior of the cell and adheres it to the cll surface. This arrangement is necessary for proper motility and completion of cell division. Adhering and positioning the flagellum are essential features of the trypanosome cell cycle that are not conserved in mammals, making these processes attractive candidates for drug intervention. We have identified the polo-like kinase homolog in T. brucei, termed TbPLK, as an essential regulator of the inheritance of a series of cytoskeletal organelles that are essential fo positioning and adhering the flagellum. Inhibiting or depleting TbPLK leads to cells with detached flagella that cannot undergo productive cell divisions. These severe and irreversible defects make TbPLK an attractive drug target and suggest that the kinase may be an important regulator of morphogenesis in trypanosomes. Identifying substrates and binding partners is an essential next step to understanding TbPLK function. These novel proteins could themselves be viable drug targets. We conducted three different proteomic screens to identify novel TbPLK interactors and substrates, which yielded 74 candidates. The work in this proposal focuses on the characterizing the function of these proteins and determining how and when they interact with TbPLK during the course of the cell cycle. Our goal is to use these newly identified proteins to establish the molecular basis for TbPLK control of morphogenesis in T. brucei.

 性状（由申请方提供）：布氏锥虫是人类非洲锥虫病和牛长角线虫病的病原体。可用于治疗锥虫病的少数有效疗法非常难以施用，并且耐药性是一个新出现的问题。很少有新药正在研究中，这使得迫切需要确定这种病原体的新疗法。锥虫是高度极化的，有一个复杂的细胞骨架，将寄生虫的单鞭毛定位在细胞的后部，并将其粘附在cll表面。这种排列对于细胞分裂的正常运动和完成是必要的。鞭毛的粘附和定位是锥虫细胞周期的基本特征，在哺乳动物中不保守，使这些过程成为药物干预的有吸引力的候选者。我们在T.布氏杆菌TbPLK是一种重要的细胞骨架细胞器的遗传调节因子，对鞭毛的定位和粘附至关重要。抑制或耗尽TbPLK导致具有分离的鞭毛的细胞不能进行生产性细胞分裂。这些严重和不可逆的缺陷使TbPLK成为一个有吸引力的药物靶点，并表明该激酶可能是锥虫形态发生的重要调节因子。识别底物和结合伴侣是了解TbPLK功能的重要下一步。这些新的蛋白质本身可能是可行的药物靶点。我们进行了三种不同的蛋白质组学筛选，以确定新的TbPLK相互作用和底物，产生了74个候选人。该提案中的工作重点是表征这些蛋白质的功能，并确定它们在细胞周期过程中如何以及何时与TbPLK相互作用。我们的目标是利用这些新发现的蛋白质建立TbPLK控制T.布鲁塞。