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Biochemical and Functional Analysis of Trypanin

锥虫蛋白酶的生化和功能分析

基本信息

批准号：
10180861
负责人：
KENT L HILL
金额：
$ 44.62万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180861
关键词：
3-Dimensional Address Adipose tissue Affect Africa South of the Sahara African Trypanosomiasis Anatomy Animals Biochemical Biology Blood - brain barrier anatomy Blood Circulation Cell division Cells Communities Cryo-electron tomography Dermis Development Disease Disease Outcome Drug Targeting Environment Eukaryota Flagella Foundations Goals Health Human Human Development Immune response Infection Infection Control Investigation Knowledge Label Livestock Mastigophora Microtubules Midgut Modeling Molecular Genetics Morbidity - disease rate Morphogenesis Mus Mutation Analysis Neuraxis Organism Parasites Pathogenesis Pathogenicity Penetration Pharmaceutical Preparations Physiology Play Proteins Protozoa Research Resolution Role Salivary Glands Series Signal Transduction Skin Tissue Structure System Testing Tissues Trypanosoma Trypanosoma brucei brucei Tsetse Flies Vaccines cell motility combat disease transmission drug discovery extracellular fly human morbidity insight interest migration molecular modeling mortality mutant novel therapeutic intervention response success three dimensional structure transmission process vector

项目摘要

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.

摘要有鞭毛的原生动物布鲁氏锥虫是非洲锥虫病的罪魁祸首，这种疾病是由采采蝇传播，并在亚热带地区造成人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，但目前还没有疫苗存在，目前的治疗方法也很陈旧，有毒且难以管理。因此，迫切需要进行研究以更好地理解这些并促进新的治疗干预措施的开发。布氏毛滴虫的细胞依赖其鞭毛运动性，信号对外部环境的反应协调，与宿主组织和细胞的相互作用形态发生和分裂。因此，锥虫的鞭毛对于寄生虫的生存、传播是必不可少的。通过苍蝇媒介和哺乳动物宿主的感染。我们研究的长期目标是理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和发病机制。关于鞭毛的组成和结构已知很多，但重要的问题仍然存在。关于构成锥虫特异性运动性的特定蛋白质和相互作用以及锥虫的作用在宿主感染期间的运动性。为了解决这些知识差距，我们将使用运动性突变体和小鼠感染模型解决运动性在避免宿主免疫反应和穿透方面的作用血管外组织，既影响疾病的发病机制，也影响疾病的传播。我们还将使用冷冻电子断层扫描，结合突变分析，建立了一个三维分子模型鞭毛和构成锥虫特有鞭毛结构和功能的阐明蛋白。我们的重点是布氏毛滴虫的鞭毛。然而，鞭毛对许多其他致病原虫很重要以及人类的正常发展和健康。因此，我们希望我们的结果会引起广泛的关注。为研究寄生原生动物的发病机制、人类发育和生理的社区，以及真核生物的基础生物学。