Biochemical and Functional Analysis of Trypanin

非洲锥虫（例如布氏锥虫）是引起非洲人睡眠的原生动物寄生虫 疾病，一种致命的疾病，具有毁灭性的健康和经济后果。这些寄生虫 二代生物，其生命周期的一部分在哺乳动物宿主中度过，一部分在昆虫载体中度过（ 采采蝇）。锥虫在生命周期的两个阶段都是高度能动的，能动性是寄生虫的中心 发展和疾病的发病机制。运动是由一个单一的鞭毛介导的， 在细胞运动、宿主-寄生虫相互作用、细胞形态发生和 细胞分裂令人惊讶的是，我们在分子水平上对鞭毛器知之甚少。在 特别是，我们缺乏对鞭毛蛋白如何组装成超分子结构的理解 以及它们如何单独和共同发挥作用，以驱动细胞运动和其他 鞭毛功能拟议研究的长期目标是促进我们对 并利用锥虫作为研究真核纤毛的模型。这将 使用功能和结构方法相结合。RNAi、定点诱变和 超微结构分析将被用来研究锥蛋白和其他成分的功能， 动力蛋白调节复合物（DRC）。DRC是信号转导途径的一部分， 运动，是必不可少的血流形式锥虫，使其成为一个候选的药物靶标。 锥虫鞭毛与其他真核生物的纤毛和鞭毛基本相同，包括 人类鞭毛是几种人类病原体运动所必需的，并且存在于大多数组织中。 人体的它们执行运动、运输和感觉功能。引起的感染性疾病 需要纤毛的病原体包括非洲昏睡病和疟疾，并导致死亡 全世界约有4亿人患病。由纤毛引起的人类遗传性疾病 缺陷包括：脑积水、不孕症、癫痫、左右轴缺陷、眼部疾病、多囊肾 疾病和肥胖。因此，除了解决细胞生物学中的基本问题外， 研究直接影响到了解和治疗传染病和遗传病的努力， 人类

African trypanosomes (e.g. Trypanosoma brucei) are protozoan parasites that cause African sleeping sickness, a fatal disease with devastating health and economic consequences. These parasites are digenetic organisms, spending part of their life cycle in a mammalian host and part in an insect vector (the tsetse fly). Trypanosomes are highly motile in both life cycle stages and motility is central to parasite development and disease pathogenesis. Motility is mediated by a single flagellum that is an essential and multifunctional organelle with critical roles in cell motility, host-parasite interaction, cell morphogenesis and cell division. Surprisingly, we know very little about the flagellar apparatus at the the molecular level. In particular, we lack an understanding of how flagellar proteins are assembled into supramolecular structures within the axoneme and how they function individually and collectively to drive cell motility and other flagellum functions. The long-term goal of the proposed research is to advance our understanding of the trypanosome flagellum and to exploit trypanosomes as a model to investigate the eukaryotic cilium. This will be done using a combination of functional and structural approaches. RNAi, site-directed mutagenesis and ultrastructural analyses will be used to investigate the function of trypanin and other components of the dynein regulatory complex (DRC). The DRC is part of a signal transduction pathway that regulates flagellar motility and is essential in bloodstream-form trypanosomes, making it a candidate drug target. The trypanosome flagellum is essentially the same as cilia and flagella in other eukaryotes, including humans. Flagella are required for motility of several human pathogens and are present on most tissues of the human body. They perform motility, transport and sensory functions. Infectious diseases caused by pathogens that require cilia include African sleeping sickness and Malaria and are responsible for mortality an morbidity in approximately 0.4 billion people world-wide. Heritable human diseases caused by cilia defects include: hydrocephalus, infertility, epilepsy, left-right axis defects, eye disorders, polycystic kidney disease and obesity. Therefore, in addition to addressing fundamental questions in cell biology, this research directly impacts efforts to understand and treat infectious diseases and genetic diseases in humans.