Structural and functional organization of the editosome in trypanosomatids

该项目的总体目标是表征控制锥虫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。锥虫是引起人类和牲畜疾病的原生寄生虫。它们包括非洲人类昏睡病、恰加斯病和利什曼病（分别为布鲁氏锥虫群、克氏锥虫和利什曼原虫种）的致病因子。由于毒性和耐药性的发展，大多数药物越来越无效。RNA编辑发生在这个家族的所有成员的锥虫病原体，它是一个潜在的化疗靶点。阐明编辑的机制、催化编辑的机制（编辑体）和编辑的调控是这一领域亟待解决的主要问题。本项目旨在了解该结构中编辑体蛋白家族的空间组织，以阐明其在T. brucei中的功能。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，旨在寻找可专利的药物，这些药物可能针对所有三种主要锥虫病原体的编辑体复合物。拟议中的项目将把麦吉尔大学的大量活动集中在RNA生物学和传染病这一令人兴奋的领域的培训和研究项目上，以实现协同作用，为应对未来新出现的疾病提供帮助。

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.