EVOLUTION OF THE NEMATODE INTESTINE, A KEY HOST INTERFACE

线虫肠道的进化，一个关键的宿主接口

• 批准号: 8087733
• 负责人: Makedonka Mitreva
• 金额: $ 25.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087733
• 关键词: Accounting; Adult; Ancylostoma (genus); Animal Feed; Anthelmintics; Ascaris suum; Automobile Driving; Bioinformatics; Biological; Birth; Brugia malayi; Categories; Cells; Cellular biology; Cessation of life; Characteristics; Child; Communities; Complementary DNA; Data; Developing Countries; Development; Diagnostic; Disease; Environment; Evolution; Family member; Foundations; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic Polymorphism; Genome; Genomics; Goals; Haemonchus; Helminths; Hookworm Infections; Hookworms; Human; Humanities; Immune; Immune system; In Situ; Infection; Intestines; Knowledge; Lead; Life; Medical; Methods; Modeling; Molecular; Molecular Models; Molecular Profiling; Morbidity - disease rate; Necator; Nematoda; Nutrient; Nutritional; Parasite Control; Parasites; Parasitic nematode; Pathogenicity; Personal Satisfaction; Pharmaceutical Preparations; Population; Poverty; Prevention; Productivity; Protein Family; Proteins; Proteome; Research; Resistance; Staging; Strongyloides; Technology; Testing; Therapeutic; Tissues; Trichinella spiralis; Trichuris; Vaccines; base; biological research; cellular targeting; chemotherapy; child physical development; comparative genomics; coping; genetic element; hazard; human morbidity; improved; knowledge of results; molecular modeling; mortality; neglect; next generation; novel; parasitism; pathogen; trait

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. PUBLIC HEALTH RELEVANCE: Parasitic nematodes are a major cause of neglected diseases in over half of the world's population, and are a leading cause of human morbidity. The main goal of this project is through implementation of comparative genomics and experimental approaches to advance principles that will have broad application to immune control of parasitic nematodes. This will be accomplished by identifying molecular and cellular features of the nematode intestine that are conserved across the Nematoda or have figured decisively in the adaptive evolution of nematode pathogens. The nematode intestine is demonstrated to be the critical interface with the host; therefore, it is the most versatile tissue for control or prevention. The gained knowledge will focus research on cellular targets with the broadest application to parasite control.

描述（由申请人提供）：超过 30 亿人，即人类的一半，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。寄生线虫降低了食用动物和农作物的生产力，而这对于经济和营养福祉至关重要，特别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可普遍应用于推进寄生虫控制的原理的澄清。我们的研究旨在通过将其划分为在线虫的整个进化过程中保留或进化的保守且多样化的遗传元件，从根本上解决这种复杂性。 我们的重点是线虫肠道，它是与宿主及其免疫系统的代谢活跃的界面。虽然它是免疫和化学治疗寄生虫控制方法的一个已被证明的目标，但人们对这个界面的保守和可变特征知之甚少。揭示线虫肠道保守性和适应性特征的进化原理将为研究界提供有效控制寄生虫的最佳目标。 该提案的三个目标集中于全面了解跨越该门进化极端的寄生虫在成虫线虫肠道中表达的基因。来自所选核心物种的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。将研究肠道蛋白质家族，以确定那些在线虫进化过程中经历出生或死亡以及扩张或收缩的蛋白质家族。最后，我们将确定肠道蛋白质家族的功能类别，这些蛋白质家族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道细胞的分子特征至关重要，这些细胞有助于在不同营养环境中获取营养，同时应对与宿主的这一关键界面接触所带来的危害。反过来，这些知识将指导通过免疫或化疗手段规避关键寄生虫功能的策略。 公共卫生相关性：寄生线虫是世界一半以上人口被忽视疾病的主要原因，也是人类发病的主要原因。该项目的主要目标是通过实施比较基因组学和实验方法来推进将广泛应用于寄生线虫免疫控制的原理。这将通过识别线虫肠道的分子和细胞特征来实现，这些特征在线虫中保守或在线虫病原体的适应性进化中起决定性作用。线虫肠道被证明是与宿主的关键界面；因此，它是用于控制或预防的最通用的组织。所获得的知识将集中于细胞目标的研究，并最广泛地应用于寄生虫控制。