Structural and functional organization of the editosome in trypanosomatids

该项目的总体目标是表征锥虫中控制线粒体基因表达和代谢的RNA编辑的基本和独特的分子过程。 锥虫是原生动物寄生虫，导致人类和牲畜的疾病。它们包括人类非洲昏睡病、恰加斯病和利什曼病（布氏锥虫群、T. cruzi和利什曼原虫物种）。 大多数药物由于毒性和耐药性的发展而越来越无效。 RNA编辑发生在锥虫病原体家族的所有成员中，是潜在的化疗靶点。 阐明编辑机制、编辑催化机制（编辑体）和编辑调控机制是编辑学研究中需要解决的主要问题。 本项目旨在提供一个家族的编辑体蛋白在这种结构中的空间组织的理解，以阐明其在T。布鲁塞。预计该项目将扩展RNA加工和基因表达机制的知识，并有助于未来的结构研究，旨在找到可能靶向所有三种主要锥虫病原体中的编辑体复合物的可专利药物。 拟议的项目将把麦吉尔大学的这一实质性活动集中在RNA生物学和传染病这一令人兴奋的领域的培训和研究计划上，以实现协同作用，为应对未来新出现的疾病做好准备。

The overall objective of this project is the characterization of an essential and unique molecular process of RNA editing that controls the mitochondrial gene expression and metabolism in trypanosomatids.  Trypanosomatids are protozoan parasites that cause diseases in humans and livestock. They include the causal agents of human African sleeping sickness, Chagas' disease, and Leishmaniases (Trypanosoma brucei group, T. cruzi, and Leishmania species, respectively).  Most drugs are increasingly ineffective due to toxicity and development of resistance.  RNA editing occurs in all members of this family of trypanosomatid pathogens and it is a potential chemotherapeutic target.  Elucidation of the mechanism of editing, the machinery that catalyzes editing (the editosome), and the regulation of editing are the major problems to be solved in this field.  This project is designed to provide an understanding of spatial organizations of a family of editosome proteins within this structure in order to elucidate its function in T. brucei. It is anticipated that this project will extend knowledge of RNA processing and gene expression mechanisms in general and contribute to future structural studies aimed at finding patentable drugs that might target the editosome complex in all three major trypanosomatid pathogens.  The proposed project will focus this substantial activity at McGill University on a training and research program in an exciting area of RNA biology and infectious diseases to achieve a synergy that will provide for responding to future emerging diseases.