Biochemical and Functional Analysis of Trypanin

描述（由申请方提供）：有鞭毛的原生动物寄生虫布氏锥虫是非洲锥虫病的病原体，导致撒哈拉以南非洲地区人类和牲畜的广泛死亡和发病。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，有毒的，难以管理。因此，迫切需要进行研究以更好地了解这些寄生虫并促进新的治疗干预措施的开发。锥虫也是研究鞭毛和纤毛生物学的重要实验系统，这对正常人类健康至关重要。T.布氏杆菌依靠鞭毛在宿主组织内运动并指导细胞发育和分裂。在广泛的真核生物中的大量工作表明，除了鞭毛在运动中的典型作用之外，它还作为信号中心来感知和响应环境中的外部线索。最近的工作表明，锥虫鞭毛同样在运动和信号能力的功能。拟议的工作的长期目标是确定运动在发病机制中的作用，确定机制，调节锥虫运动和测试的假设，鞭毛指导信号系统的重要毒力。为此，我们将采用运动突变体，小鼠感染模型来测试信号传导和运动功能对感染的贡献。我们还将采用系统生物学方法来定义鞭毛中的信号系统，并确定由这些信号系统控制的基因。最后，我们将使用冷冻电子断层扫描，连同突变分析，以建立一个三维的鞭毛的分子模型，努力了解独特的鞭毛功能锥虫的结构基础。我们的重点是T.布鲁塞。然而，鞭毛对许多其他致病性原生动物以及正常的人类发育和健康都很重要。因此，我们希望我们的研究结果是广泛的兴趣，为社会研究寄生原生动物的发病机制，人类发育和生理，以及真核生物的基础生物学。

DESCRIPTION (provided by applicant): The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis, which 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, ther is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. Trypanosomes are also an important experimental system for studying biology of flagella and cilia, which are critical to normal human health. T. brucei depends on its flagellum for movement within host tissues and for directing cell development and division. Extensive work in a wide range of eukaryotes demonstrates that in addition to the flagellum's canonical role in motility, it functions as a signaling center to perceive and respond o external cues in the environment. Recent work indicates that the trypanosome flagellum likewise functions in motility and signaling capacity. The long term goal of the proposed work is to determine the role of motility in pathogenesis, define mechanisms that regulate trypanosome motility and test the hypothesis that the flagellum directs signaling systems important for virulence. To do this, we will employ motility mutants, mouse infection models to test signaling and motility functions for a contribution to infection. We will also employ systems biology approaches to define signaling systems in the flagellum and identify genes controlled by these signaling systems. Finally, we will use cryoelectron tomography, together with mutational analysis to build a three-dimensional molecular model of the flagellum in an effort to understand structural foundations of unique flagellum functions in trypanosomes. 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.