Centrosome control of Toxoplasma growth

弓形虫生长的中心体控制

• 批准号: 9185938
• 负责人: Michael W White
• 金额: $ 46.15万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 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/9185938
• 关键词: Animals; Apicomplexa; Biogenesis; Cell Cycle; Cell Cycle Regulation; Cell division; Cell model; 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; Genetic study; Growth; Host Defense; Human; Infection; Investigation; Knowledge; Lead; Longevity; Mitosis; Molecular; Mothers; Organelles; Parasite Control; Parasites; Pharmacotherapy; Phosphotransferases; Process; Protein Kinase; Proteins; Protozoa; Regulation; Role; Scheme; Site; Structural Protein; Structure; Therapeutic Intervention; Toxoplasma; Toxoplasma gondii; Vitronectin; base; chromosome replication; effective therapy; experimental study; flexibility; novel; novel therapeutic intervention; novel therapeutics; parasite invasion; pressure; protein biomarkers; public health relevance; reverse genetics; temperature sensitive mutant; transmission process

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）：顶复门寄生虫具有与其人类宿主不同的特化细胞周期。与动物细胞分裂不同， 新的顶复门寄生虫遵循灵活的分裂方案，在消耗母细胞的复杂出芽过程中组装许多子寄生虫。了解这种不寻常的寄生虫细胞周期的分子基础是可取的， 这些知识将产生的潜在新疗法。对弓形虫速殖子复制的研究已经确定了主要的细胞周期分裂，并建立了产生感染性寄生虫所需的细胞骨架组装的基本步骤。速殖子是一个经过验证的模型，在顶复门细胞周期的调查，因为他们经历简单的二元分裂与单轮的染色体复制，然后并发有丝分裂和寄生虫出芽。随着速殖子生长的主要形态发生步骤的定义，我们现在可以解开他们的基本细胞周期机制的上下文中的调节的分子基础。在这个应用中，我们将利用强大的弓形虫遗传模型来表征寄生虫细胞周期的中心体为基础的调节。我们假设中心体是真核细胞周期控制的保守特征与寄生虫特异性组装传播所需的专门的入侵感受态子细胞的过程相协调的中心细胞器。为了理解中心体和出芽周期的分子基础，我们提出了两个目标。在目标1中，我们将解释中心体生物发生和关键结构蛋白在寄生虫出芽起始中的作用。在目标2中，我们将描述通过中心体和相关结构控制胞质分裂和有丝分裂的细胞周期激酶。拟议的实验将扩大我们的知识如何apicomplexan细胞周期的调节。这两个目标代表了互补的方法，其中中心体生物发生的结构框架的发展将为理解中心体和内部出芽周期的蛋白激酶调控提供细胞周期背景。该项目有可能发现寄生虫生长所需的新因素，未来可能会利用这些因素来开发新的治疗干预策略。