EVOLUTION OF THE NEMATODE INTESTINE, A KEY HOST INTERFACE

描述（由申请人提供）：超过30亿人，占人类的一半，感染了寄生线虫。这些病原体是被忽视疾病的主要病原体，导致人类死亡和发病，并干扰儿童的正常发育。寄生线虫降低了对经济和营养福祉至关重要的食用动物和作物的生产力，尤其是对发展中国家的人民而言。线虫的生物学和基因组复杂性阻碍了对促进寄生虫控制的普遍应用原理的澄清。我们的研究旨在通过将其划分为保守的和多样化的遗传元素来解决这种复杂性，这些遗传元素在线虫的进化过程中被保留或进化。我们的重点是线虫的肠道，这是与宿主及其免疫系统代谢活跃的界面。虽然它已被证明是免疫和化疗方法控制寄生虫的靶点，但人们对该界面的保守性和可变特征知之甚少。揭示线虫肠道的保守性和适应性特征背后的进化原理将为研究群体提供有效控制寄生虫的最佳目标。本提案的三个目标集中在提供一个全面的理解，在成年线虫肠中表达的基因，从寄生虫跨越门的进化极端。从选定的核心物种肠道转录组将用于确定泛线虫肠道转录组。先进的生物信息学方法将应用于从所有其他可用的线虫基因组中描绘肠道基因，强调人类病原体太小而无法支持直接分析肠道功能。将对肠道蛋白家族进行调查，以确定在线虫进化过程中经历过出生或死亡以及扩张或收缩的家族。最后，我们将确定肠道蛋白家族的功能类别，这些功能类别反映了寄生进化中最重要的适应性特征。由此产生的知识对于了解线虫肠细胞的分子特征至关重要，这些特征有助于在不同的营养环境中获取营养，同时应对暴露在与宿主的关键界面上所带来的危害。反过来，这些知识将指导通过免疫或化疗手段规避寄生虫关键功能的策略。

DESCRIPTION (provided by applicant): More than three billion people, one-half of humanity, are infected with parasitic nematodes. These pathogens are the main causative agents of neglected diseases, causing mortality and morbidity in humans and interfering with normal development in children. Parasitic nematodes reduce productivity of food animals and crops which are critical for economical and nutritional well-being, especially for people in developing countries. The biological and genomic complexity of nematodes has impeded the clarification of principles that could have general application towards advancing parasite control. Our research is intended to resolve this complexity substantially by partitioning it into conserved and diverse genetic elements that have been retained or have evolved throughout the evolution of the Nematoda. Our focus is on the nematode intestine, which is a metabolically active interface with the host and its immune system. While it is a demonstrated target for both immune- and chemo-therapeutic approaches to parasite control, very little is known regarding the conserved and variable features of this interface. Uncovering the evolutionary principles underlying both conserved and adaptable features of the nematode intestine will provide the research community with optimal targets for effective parasite control. The three aims in this proposal focus on providing a comprehensive understanding of genes that are expressed in the adult nematode intestine from parasites that span the evolutionary extremes of the phylum. The intestinal transcriptomes from the selected core species will be used to determine the pan-Nematoda intestinal transcriptome. Advanced bioinformatic approaches will be applied to delineate intestinal genes from all other available nematode genomes, emphasizing human pathogens that are too small to support direct analysis of intestinal functions. Intestinal protein families will be investigated to identify those that have undergone births or deaths and expansions or contractions throughout nematode evolution. Finally, we will determine functional categories of intestinal protein families that reflect adaptable traits of the highest importance in evolution of parasitism. Resulting knowledge is essential to understand molecular features of nematode intestinal cells that facilitate nutrient acquisition in diverse trophic environments, while coping with hazards that accompany exposure at this key interface with the host. In turn, that knowledge will guide strategies to circumvent critical parasite functions by immunological or chemotherapeutic means.