Centrosome control of Toxoplasma growth

弓形虫生长的中心体控制

基本信息

批准号：
8643435
负责人：
Michael W White
金额：
$ 48.8万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643435
关键词：
Animals Apicomplexa Biogenesis Cell Cycle Cell Cycle Regulation Cell division Cells Centrioles Centrosome Cessation of life Chromosome Segregation Clinical Treatment Complement Complex Core Protein Cytokinesis Cytolysis Daughter Development Disease Drug resistance Eukaryotic Cell Fiber Future Genetic Models Growth Host Defense Human Infection Investigation Knowledge Lead Longevity Mitosis Modeling Molecular Mothers Organelles Parasite Control Parasites Pharmaceutical Preparations Phosphotransferases Process Protein Kinase Proteins Protozoa Regulation Role Scheme Site Structural Protein Structure Therapeutic Intervention Toxoplasma Toxoplasma gondii base chromosome replication effective therapy flexibility novel parasite invasion positional cloning pressure public health relevance research study temperature sensitive mutant transmission process

项目摘要

DESCRIPTION (provided by applicant): Apicomplexan parasites have specialized cell cycles that are distinct from their human host. Unlike animal cell division, which results from fission of the mother into two daughters, new Apicomplexa parasites follow flexible, division schemes that assemble numerous daughter parasites in a complex budding process that consumes the mother cell. Understanding the molecular basis of this unusual parasite cell cycle is desirable for the potential new therapies this knowledge will yield. Studies of Toxoplasma gondii tachyzoite replication have defined the major cell cycle divisions and established the basic steps of cytoskeletal assembly required to produce infectious parasites. Tachyzoites are a proven model for cell cycle investigations in the Apicomplexa as they undergo simple binary division with a single round of chromosome replication followed by concurrent mitosis and parasite budding. With the major morphogenic steps of tachyzoite growth defined, we can now unravel the molecular basis of their regulation in the context of basic cell cycle mechanisms. In this application, we will exploit robust Toxoplasma genetic models to characterize centrosome-based regulation of the parasite cell cycle. We hypothesize that the centrosome is the central organelle coordinating conserved features of eukaryotic cell cycle control with the parasite specific process of assembling the specialized invasion competent zoite cell required for transmission. To understand the molecular basis of the centrosome and budding cycles, we propose two aims. In aim 1 we will decipher centrosome biogenesis and the role of key structural proteins in the initiation of parasite budding. In aim 2, we will characterize cell cycl kinases that operate through the centrosome and associated structures to control cytokinesis and mitosis. The proposed experiments will expand our knowledge of how the apicomplexan cell cycle is regulated. The two aims represent complimentary approaches where the development of a structural framework for centrosome biogenesis will provide the cell cycle context for understanding protein kinase regulation of the centrosome and internal budding cycles. This project has the potential to discover new factors required for parasite growth that may be exploited in the future to develop new strategies for therapeutic intervention.

描述（由申请人提供）：Apicomplexan寄生虫具有与人类宿主不同的专门细胞周期。与动物细胞分裂不同，这是由于裂变而产生的母亲成为两个女儿，新的Apicomplexa寄生虫遵循灵活的分裂计划，这些计划在一个复杂的萌芽过程中组装了许多女儿寄生虫，该过程消耗了母细胞。理解这种不寻常的寄生虫细胞周期的分子基础是需要的这种知识将产生的潜在新疗法。弓形虫弓形虫的研究已定义了主要的细胞周期分裂，并确定了产生传染性寄生虫所需的细胞骨架组件的基本步骤。 tachyzoites是APICOMPLEXA中细胞周期研究的验证模型，因为它们进行了简单的二元分裂，并进行了一轮染色体复制，然后同时进行有丝分裂和寄生虫出芽。通过定义速氮岩生长的主要形态学步骤，我们现在可以在基本细胞周期机制的背景下揭示其调节的分子基础。在此应用中，我们将利用强大的弓形虫遗传模型来表征基于中心体的寄生虫细胞周期的调节。我们假设中心体是真核细胞周期控制的中央细胞器协调的保守特征，该特征与寄生虫的特定过程组装了专门的入侵合作的Zoite Zoite细胞。为了了解中心体和萌芽周期的分子基础，我们提出了两个目标。在AIM 1中，我们将破译中心体的生物发生以及关键结构蛋白在寄生虫发芽中的作用。在AIM 2中，我们将表征通过中心体和相关结构控制细胞因子和有丝分裂的相关结构的细胞CYCL激酶。提出的实验将扩展我们对如何调节Apicomplexan细胞周期的了解。这两个目的代表了免费的方法，其中开发了中心体生物发生的结构框架将为理解中心体和内部发芽周期的蛋白激酶调节提供细胞周期环境。该项目有可能发现寄生虫增长所需的新因素，这些因素将来可能会利用，以制定新的治疗干预策略。