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: 9356517
• 负责人: Makedonka Mitreva
• 金额: $ 27.55万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356517
• 关键词: Address; Agriculture; Animal Feed; Animals; Anthelmintics; Apical; Architecture; Ascaris suum; Bioinformatics; Biological; Biological Models; Blood; Carrier Proteins; Cell Survival; Cell model; Cell physiology; Cells; Chemicals; Child; Child Development; Clinical; Databases; Developing Countries; Development; Disease; Elements; Evolution; Exocytosis; Experimental Models; Foundations; Genes; Goals; Haemonchus; Human; In Vitro; Infection; Intervention; Intestines; Investigation; Knowledge; Lead; Link; Membrane; Methods; Microtubules; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Nematoda; Nematode infections; Nutritional; Parasites; Parasitic nematode; Pathway interactions; Perfusion; Pharmaceutical Preparations; Population; Poverty; Process; Productivity; Proteins; Research; Research Personnel; Resistance; Resources; Role; Scheme; Soil; Solid; System; Testing; Therapeutic; Tissues; Trichuris; Vaccines; Validation; Vesicle Transport Pathway; base; benzimidazole; chemical property; cheminformatics; design; disorder control; drug development; drug testing; efficacy testing; feeding; improved; in vivo; in vivo Model; inhibitor/antagonist; large-scale database; mortality; neglect; new therapeutic target; novel; novel therapeutics; pathogen; prospective; protein transport; success; systems research; therapeutic target

Evolution of the nematode intestine: a critical host interface Abstract More than two billion people are infected with parasitic nematodes. These pathogens are a major cause of neglected diseases that lead to mortality and diverse forms of morbidity in humans, while 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 control and treatment of these infections is challenged by the absence of vaccines, the limited choice of anthelmintics and evolution of anthelmintic resistance in these pathogens. The biological and molecular complexity of nematodes has further impeded research on development of new therapies for treatment and control. Our research focuses on the versatility of the nematode intestine as a target for new therapies. Our recent progress has established a broad and deep understanding of the molecular architecture underlying intestinal cell functions at the pan-Nematoda level. We also developed a new experimental model to investigate essential features of the nematode intestine as it relates to pan-Nematoda development of new targets for therapies to treat and control these pathogens in humans and animals. Progress to date has formed a solid foundation upon which the current proposal will capitalize in advancing capabilities to thoroughly investigate the potential of nematode intestinal functions in providing new therapies for nematode infections. Using the multi-omics resource that we have built, we will develop computational schema to identify and prioritize pan-Nematoda proteins/pathways that warrant investigation as anthelmintic targets (Aim 1). Druggable targets among prioritized proteins/pathways will be identified, followed by a systematic identification of inhibitors that can be experimentally evaluated using existing and emerging model systems (Aim 2). Aims 1 and 2 will generate the first large-scale databases of this kind for nematodes, which will have exceptionally high value for our research and that of many other investigators. Preliminary results identified microtubule-dependent apical exocytosis as a high priority process for investigation, which will be investigated in Aim 3, utilizing the Ascaris suum intestinal cell and perfusion model. This research will establish an experimental system to thoroughly investigate apical exocytosis, evaluate chemical inhibitors of this pathway and test inhibitors of other pathways identified from Aims 1 and 2. In Aim 4, progress made in preceding aims will be extended to two other core species, Haemonchus contortus and Trichuris suis, to assess the pan-Nematoda application of findings related to conserved intestinal cell processes and inhibitors. Advances are expected in establishing a new paradigm in research on parasitic nematodes that is designed to have pan-Nematoda application. Extensive databases resulting from secondary and tertiary integration of existing information offers unprecedented guidance for researchers in the field. That information will be used to guide experimental approaches for the purpose of validating predictions and testing efficacy of inhibitors that may reflect initial progress toward development of new broad spectrum anthelmintics.

线虫肠道的进化：一个关键的宿主界面 摘要 超过20亿人感染了寄生线虫。这些病原体是导致 被忽视的疾病，导致人类死亡和各种形式的发病，同时干扰 儿童的正常发育。寄生线虫降低食用动物和作物的生产力， 对经济和营养福祉至关重要，特别是对发展中国家的人民。控制和 这些感染的治疗受到缺乏疫苗、驱虫药选择有限以及 这些病原体对驱虫药耐药性的演变。线虫的生物学和分子复杂性 进一步阻碍了用于治疗和控制的新疗法的开发研究。我们的研究 重点是线虫肠道作为新疗法靶点的多功能性。我们最近的进展 建立了广泛而深入的了解分子结构的基础肠细胞功能， 泛线虫水平。我们还开发了一种新的实验模型来研究 线虫肠，因为它涉及到泛线虫类开发新的治疗和控制目标 这些病原体在人类和动物中。 迄今取得的进展已奠定了坚实的基础，目前的建议将在此基础上加以利用， 提高能力，彻底调查线虫肠道功能的潜力， 线虫感染的治疗方法。利用我们已经建立的多组学资源，我们将开发 计算模式，以确定和优先考虑泛线虫蛋白质/途径，值得调查， 驱虫目标（目标1）。将确定优先蛋白质/途径中的可药物靶点， 通过系统地鉴定抑制剂，可以使用现有的和新兴的 模型系统（目标2）。目标1和2将建立第一个大型线虫数据库， 这将对我们的研究和许多其他研究人员的研究具有非常高的价值。初步 结果表明，微管依赖的顶端胞吐作用是一个高优先级的研究过程， 目的3利用猪蛔虫肠细胞模型和灌流模型进行研究。这项研究将 建立了一个实验系统，以彻底研究顶端胞吐，评价化学抑制剂， 本发明还提供了该途径的抑制剂和从目的1和2鉴定的其它途径的测试抑制剂。在目标4中， 上述目标将扩展到另外两个核心物种，捻转血矛线虫和猪鞭虫， 评估与保守的肠细胞过程和抑制剂有关的发现在泛线虫类中的应用。 在建立寄生线虫研究的新范式方面有望取得进展， 设计成具有泛线虫应用。二级和三级教育产生的广泛数据库 现有信息的整合为该领域的研究人员提供了前所未有的指导。该信息 将用于指导实验方法，以验证预测和测试的功效 抑制剂，可能反映了新的广谱驱虫药的开发的初步进展。