Developmental regulation of mitochondrial RNA editing in trypanosomes

锥虫虫属相关的单细胞寄生生物，可导致非洲昏睡病、恰加斯病和利什曼病等严重的人类疾病。例如，布鲁氏锥虫是一种血液，细胞外病原体，影响中枢神经系统并导致人类昏睡病。光是布氏绦虫的死亡率每年就有48 000人，每年损失150万残疾调整生命年。这些疾病也通过移民和归国士兵的输血和器官捐献传入西方世界。这种媒介传播的寄生虫在其复杂的生命周期中生存，广泛依赖于数百个基因的精细调控。这包括它们线粒体基因的差异表达，这代表了一个与哺乳动物（宿主）或其他后生动物和原生动物生物高度分化的系统。我们假设，了解这些致命病原体中基因表达的调控对于理解它们的生物学和鉴定可能在多种锥虫病原体中共享的关键调控模块（可能是药物靶点）至关重要。在短期内，本研究将确定和表征在布氏体生命阶段负责ATP生成不同机制的基本因子（调节因子）。为此，我们将使用我们的计算工具以及实验方法来确定在转换过程中调节事件的因素。这项研究的长期目标是提供调节能量产生的分子网络的全球地图。由于这一网络在传播、传染性和疾病方面发挥着不可或缺的作用，该项目将为未来治疗锥虫病铺平道路。

Trypanosomatid species are related parasitic unicellular organisms that are responsible for serious human diseases such as African sleeping sickness, Chagas' disease, and leishmaniasis. Trypanosoma brucei for instance is a bloodstream, extracellular pathogen that affects the central nervous system and causes human sleeping sickness. T. brucei mortality rate alone is 48,000 individuals per year and has an annual loss of 1.5 million disability-adjusted life years (DALYs). These diseases have also been introduced to the western world by blood transfusion and organ donation of immigrants and returning soldiers. The survival of this vector-borne parasite through its intricate life cycle is extensively dependent on the fine regulation of hundreds of genes. This includes, differential expression of their mitochondrial genes, representing a highly diverged system from those of mammals (hosts) or other metazoan and protozoan organisms. We hypothesize that understanding the regulation of gene expression in these lethal pathogens is essential to understanding their biology and identification of key regulatory modules (likely drug targets) that may be shared in multiple trypanosomatid pathogens. In the short term, this research will identify and characterize the essential factors (regulators) responsible for differential mechanisms of ATP generation during the life-stages of T. brucei. For this purpose, we will use our computational tools along with experimental approaches to identify factors that modulate the events during transition. The long term goal of this research is to provide a global map of the molecular network that regulates the energy production. As this network plays indispensable roles in transmission, infectivity and disease, this project will pave the way for much needed future therapeutics against trypanosomatids.