EVOLUTION OF THE NEMATODE INTESTINE, A KEY HOST INTERFACE

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。这些病原体是引起 在人类中导致死亡和各种形式的发病率的被忽视的疾病，同时干扰 儿童发育正常。寄生线虫会降低食用动物和农作物的生产力 对经济和营养福祉至关重要，特别是对发展中国家的人民来说。控件和 这些感染的治疗面临着缺乏疫苗、驱虫剂选择有限和 这些病原菌对驱虫药耐药性的进化。线虫的生物学和分子复杂性 进一步阻碍了治疗和控制新疗法的开发研究。我们的研究 重点是线虫肠道的多功能性，作为新疗法的目标。我们最近的进展是 建立了对支持肠道细胞功能的分子结构的广泛和深入的理解 泛线虫级别。我们还开发了一个新的实验模型来研究 肠道线虫与泛线虫的关系为治疗和控制开发新的靶点 这些病原体存在于人类和动物体内。 迄今取得的进展奠定了坚实的基础，本提案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，提供新的 线虫感染的治疗方法。利用我们已经建立的多元组学资源，我们将开发 识别和优先处理需要研究的泛线虫蛋白质/途径的计算模式 驱虫目标(目标1)。将确定优先蛋白质/途径中的可用药靶点，并遵循 通过系统地鉴定可以使用现有的和新出现的抑制剂进行实验评估的抑制剂 模型系统(目标2)。AIMS 1和AIMS 2将产生第一个这种线虫的大规模数据库， 这将对我们的研究和许多其他调查人员的研究具有非常高的价值。初步 结果确定微管依赖的心尖部胞吐是一个高度优先的研究过程，它将 目的3，利用猪蛔虫肠道细胞和灌流模型进行研究。这项研究将 建立深入研究心尖部胞吐作用的实验系统，评价化学抑制剂 这一途径和从目标1和2中确定的其他途径的测试抑制剂。在目标4中，在 上述目标将扩展到另外两个核心物种，扭曲血吸虫和猪旋毛虫，以 评估泛线虫对保守的肠道细胞过程和抑制物研究结果的应用。 在建立寄生线虫研究的新范式方面有望取得进展 专为泛线虫应用而设计。第二级和第三级产生的大量数据库 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。这些信息 将用于指导实验方法，目的是验证预测和测试 可能反映新的广谱驱虫药开发的初步进展的抑制剂。

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.