Biochemical and Functional Analysis of Trypanin

摘要 有鞭毛的原生动物寄生虫布氏锥虫是非洲锥虫病的罪魁祸首， 由采采蝇传播，并在亚热带地区引起人类和牲畜的广泛死亡和发病。 撒哈拉非洲。昏睡病如果不治疗是致命的，但没有疫苗存在，目前的治疗方法是旧的， 有毒且难以施用。因此，迫切需要进行研究，以更好地了解这些 寄生虫和促进新的治疗干预措施的发展。T.布鲁氏菌依靠鞭毛作为细胞 运动性、响应于外部环境的信号传导的协调、与宿主组织和细胞的相互作用 形态发生和分裂。因此，锥虫鞭毛对寄生虫的生存、传播和繁殖至关重要。 通过蝇媒和感染哺乳动物宿主。我们研究的长期目标是了解 锥虫鞭毛提供的运动性和宿主-寄生虫相互作用如何促进感染， 发病机制我们对鞭毛的组成和结构了解很多，但仍存在一些重要的问题 关于特定的蛋白质和相互作用的基础锥虫特异性运动和作用， 在宿主感染期间的运动性。为了解决这些知识差距，我们将采用运动突变体和小鼠 感染模型，以解决运动性在避免宿主免疫应答和渗透中的作用。 血管外组织，这两者都影响疾病的发病机制和传播。我们还将使用 冷冻电子断层扫描，连同突变分析，建立一个三维分子模型， 鞭毛和阐明蛋白质，包括锥虫特异性鞭毛的结构和功能。 我们的重点是T.布鲁塞。然而，鞭毛对于许多其他病原性原生动物是重要的 以及正常的人类发育和健康。因此，我们希望我们的结果能引起广泛的兴趣 为研究寄生原生动物的发病机理、人类发育和生理的社区， 真核生物基础生物学

Abstract The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis, which is transmitted by the tsetse fly and causes widespread mortality and morbidity of humans and livestock in sub- Saharan Africa. Sleeping sickness is fatal if untreated, yet no vaccine exists and current treatments are old, toxic and difficult to administer. Thus, there is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. T. brucei depends on its flagellum for cell motility, coordination of signaling in response to the external environment, interaction with host tissues, and cell morphogenesis and division. Thus, the trypanosome flagellum is essential for parasite survival, transmission through the fly vector, and infection of the mammalian host. The long-term goal of our studies is to understand how motility and host-parasite interactions provided by the trypanosome flagellum contribute to infection and pathogenesis. Much is known about flagellum composition and structure, but important questions remain regarding the specific proteins and interactions that underlie trypanosome-specific motility and the role of motility during host infection. To address these knowledge gaps, we will employ motility mutants and mouse infection models to address the role of motility in avoidance of the host immune response and penetration of extravascular tissues, which both impact disease pathogenesis and transmission. We will also use cryoelectron tomography, together with mutational analysis, to build a three-dimensional molecular model of the flagellum and elucidate proteins that comprise trypanosome-specific flagellum structures and functions. Our focus is on the flagellum of T. brucei. However, flagella are important for many other pathogenic protozoa as well as for normal human development and health. Therefore, we expect our results to be of wide interest for the community studying pathogenesis of parasitic protozoa, human development and physiology, and fundamental biology of eukaryotes.