自然和人工诱导布氏锥虫分化的分子机理

Trypanosoma brucei is the pathogen of human sleeping sickness and animal Nagana disease. This parasite is one of the most important tropical zoonotic pathogens which are strongly required to be controlled and eliminated around the world by WHO. In addition, T. brucei is also one of the well-known and well investigated parasitic organisms particularly in the relationship between host and parasite. Similar to other eukaryotic pathogens, because of the lack of vaccine, chemotherapy is still the key step for the control of sleeping sickness and Nagada disease as well as other animal trypanosomiasis in the endemic regions. However,the long term use of a few compounds has resulted in strong resistance to these compounds and caused less effective for treatment. It is well known that the differentiation of T. brucei from dividing slender to non-dividing stumpy forms is the key stage for infection and transmssion to insect vector. It is also an idea targeting stage for control. Although lot of work have been done on the differentiaton of T. brucei based on the natural and artifical conditions, little is known regaring the molecular mechanism of differentiation of this parasite from slender to stumpy forms. Here, we are planning to sequence and compare the transcriptomes of coding and non-coding RNA of T. brucei before and after differentiation in natural and artifical treatment and to identify the key factors and related genes which are linked to the differentiation. Data from this project will be greatly benefitted for understading the molecular mechanism of differentiation of T. brucei and will provide valuable molecular information to develop the new drugs for against trypanosomiasis in human and animals.

布氏锥虫是人睡眠病和动物锥虫病的病原体，是WHO和OIE致力要在全球控制的重要人畜共患热带病病原体之一，也是国际学术界研究宿主与寄生原虫相互关系的重要模式物种。药物治疗锥虫病目前仍是WHO优先选择的方法之一，但由于长期使用为数不多的几种抗锥虫药，许多流行区虫株已对其出现严重的抗性，导致治疗失败。布氏锥虫从分裂的细长型分化成没有分裂能力的粗短型是其传播的关键，也是其生活史在哺乳动物和人中最薄弱的环节。尽管人们对锥虫的分化包括人工诱导分化作了大量的研究，但其精确机理迄今未明。本项目拟在自然和人工诱导的条件下，对布氏锥虫从细长型分化成粗短型的编码和非编码RNA的转录组进行大规模测序分析，通过基因剔除和RNAi技术明确诱导布氏锥虫分化的关键分子和相关基因及其功能，为研究针对诱导锥虫分化的新型药物的研发提供全新的理论基础。

布氏锥虫（Trypanosoma brucei）是人睡眠病和动物锥虫病的病原体，是WHO和OIE致力要在全球控制的重要人畜共患热带病病原体之一，也是国际学术界研究宿主与寄生原虫相互关系的重要模式物种。药物治疗锥虫病目前仍是WHO优先选择的方法之一，但由于长期使用为数不多的几种抗锥虫药，许多流行区虫株已对其出现严重的抗性，导致治疗失败。布氏锥虫从分裂的细长型分化成没有分裂能力的粗短型是其传播的关键，也是其生活史最薄弱的环节。尽管人们对锥虫的分裂分化包括人工诱导分化作了大量的研究，但精确机理迄今未明。本项目主要目的是在体内外（自然和人工诱导）的条件下了解布氏锥虫的分裂和分化（从分裂的细长型分化成没有分裂能力但有感染媒介宿主能力的粗短型）的分子机理。重要成果主要表现为：（1）证明布氏锥虫的CIF1和Polo-like激酶在其胞质分裂中发挥重要作用，成果发表在PNAS(2016)。（2）发现布氏锥虫在其生活史的分化发育中，ATP驱使和AMPK独立的自噬对其适应新的环境起到重要作用（Autophagy，2017）.（3）通过将布氏锥虫在小鼠体内半年的快速传代，成功地使具有细长型和粗短型的布氏锥虫Antat1.1虫株从多态型(polymorphic)变成只有细长型的单态型(monomorphic)，而且单态型锥虫表现出对小鼠的毒力明显增强，体外（27o C)转化成前循环型（procyclic form）能力明显减弱的生物学特性。 通过对细长型和粗短型的编码和非编码RNA的转录组进行大规模测序分析，发现POMP和PAD等基因发生明显的变化（成果在撰写论文和待发表中）。这些基因的显著变化对我们深入了解布氏锥虫在哺乳动物体内的分化提供了重要的分子信息。研究结果为精确了解布氏锥虫的分化调控和研发新型的抗锥虫药物提供了新的理论基础。