Centrosome control of Toxoplasma growth

描述(申请人提供)：Apicomplexan寄生虫具有与其人类宿主不同的特殊细胞周期。与动物细胞分裂不同的是，动物细胞分裂是由 新的Apicomplexa寄生虫将母亲分成两个女儿，遵循灵活的分裂方案，在一个复杂的萌芽过程中组装大量的女儿寄生虫，这个过程消耗了母细胞。了解这种不同寻常的寄生虫细胞周期的分子基础对于 这些知识将产生潜在的新疗法。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，并建立了产生传染性寄生虫所需的细胞骨架组装的基本步骤。速殖子是一种成熟的细胞周期研究模型，因为它们经历了简单的二元分裂，只需一轮染色体复制，然后同时进行有丝分裂和寄生虫发芽。随着速殖子生长的主要形态发生步骤的确定，我们现在可以在基本的细胞周期机制的背景下揭开它们调控的分子基础。在这个应用中，我们将利用强大的弓形虫遗传模型来表征基于中心体的寄生虫细胞周期调控。我们假设中心体是中央细胞器，协调真核细胞周期控制的保守特征与寄生虫特有的组装传播所需的特殊侵袭能力的带状细胞的过程。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。在目标1中，我们将破译中心体的生物发生和关键结构蛋白在寄生虫发芽启动中的作用。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蛋白激酶。拟议中的实验将扩大我们对顶端复合体细胞周期是如何调节的知识。这两个目标是互补的方法，中心体生物发生结构框架的发展将为理解中心体和内部萌发周期的蛋白激酶调节提供细胞周期背景。该项目有可能发现寄生虫生长所需的新因素，这些因素可能在未来被利用来开发新的治疗干预策略。

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.