权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.