Development of essential research tools for sustaining global programs for the elimination of human hookworms

开发基本研究工具以维持消除人类钩虫的全球计划

• 批准号: 10555769
• 负责人: Rachel Fath Daniels
• 金额: $ 25.35万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555769
• 关键词: Address; Animal Model; Anthelmintics; Applied Genetics; Biochemistry; Biological; Biology; Clinical; Communicable Diseases; Deposition; Development; Disease; Drug resistance; Failure; Female; Future; Gelatin; Genes; Genetic; Genetic Materials; Genetic Polymorphism; Genome; Genomic approach; Goals; Health; Helminths; Hookworms; Human; Inbreeding; Investigation; Lead; Medical; Mission; Modeling; Multi-Drug Resistance; Nematoda; Outcome; Parasites; Partner in relationship; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Public Health; Research; Resistance; Resources; Soil; Source; System; United States National Institutes of Health; burden of illness; canine model; capsule; deep sequencing; diagnostic tool; disability; genetic architecture; genomic locus; global health; improved; innovation; jejunum; male; neglect; novel; novel diagnostics; pathogen; prevent; programs; resistance gene; response; risk minimization; tool; trait; translational model

Hookworm genomes are currently poorly assembled and remain highly fragmented making it impossible to determine changes in the genetic architecture in response to drug treatment, and thus to identify genes associated with drug resistance. The long-term goal is to directly inform global health strategies for mitigating and addressing drug resistance in soil-transmitted helminth (STH) parasites using both clinically applied and genetic/genomic approaches. The overall objective of this application is to develop research tools for sustaining global programs for the elimination of human hookworms as a public health problem. The rationale for this research is that developing an optimal animal model and producing a highly contiguous genome assembly for hookworms will allow identification of resistance loci and the development of new diagnostics to support and sustain global mass drug administration programs (MDA). We propose two specific aims: 1) Develop a novel canine model to support investigations into hookworm biology and genetics and 2) Produce a highly contiguous genome assembly for A. caninum. In the first aim, a novel system for performing single-pair matings of A. caninum hookworms will be developed whereby a pair of male/female immature worms will be placed in a gelatin capsule that will be deposited in the mid-jejunum via endoscopic guided delivery. High levels of polymorphism in nematodes limit the contiguity of genome assemblies, thus we will use this model to produce a new inbred line with reduced polymorphism. For the second aim, inbred worms will serve as the source of genetic material for deep sequencing using long-read sequencing together with short-read approaches to produce a highly contiguous genome assembly. The research proposed in this application is innovative because we will develop an experimentally tractable and natural host model with well-described physiology and biochemistry, making it an excellent translational model for human hookworms. Furthermore, naturally evolved multiple-drug resistant isolates of A. caninum already exist and are readily available, providing the source genetic material to interrogate the genetic loci involved with resistance. Similar biologic resources and a model to exploit them for discovery do not currently exist for human hookworms. The proposed research is significant because it is expected to provide essential resources and improve the technical capability for studying the biology and genetics of drug resistance and other important traits in a largely neglected, but medically relevant pathogen. Ultimately, the resources created in this research will facilitate future investigations to develop the research and diagnostic tools necessary to support and sustain global programs for the elimination of human hookworms as a public health problem. These outcomes are anticipated to have a positive impact on the health and well-being of persons living in hookworm-endemic regions by improving the sustainability of MDA strategies, making it possible to both eliminate disease from STH while minimizing the risks of long-term program failure due to anthelmintic resistance.

钩虫基因组目前组装不良，仍然高度碎片化，使其不可能 确定响应药物治疗的遗传结构的变化，从而识别相关基因 有抗药性。长期目标是直接为全球卫生战略提供信息， 使用临床应用和遗传/基因组方法研究土传蠕虫（STH）寄生虫的耐药性 接近。这项申请的总体目标是开发研究工具，以维持全球项目， 消灭人类钩虫是一个公共卫生问题。这项研究的基本原理是， 一个最佳的动物模型和生产一个高度连续的钩虫基因组组装将允许 确定耐药基因座和开发新的诊断方法，以支持和维持全球大规模药物 管理程序（MDA）。我们提出了两个具体的目标：1）开发一种新的犬模型，以支持 钩虫生物学和遗传学研究; 2）产生A. 犬的在第一个目标中，一个新的系统进行单对交配的A。犬钩虫将是 一对雄性/雌性未成熟的蠕虫将被放置在一个明胶胶囊中， 通过内窥镜引导输送到空肠中段。线虫的高度多态性限制了 因此，我们将使用该模型来产生具有减少的多态性的新自交系。为 第二个目标是，近交蠕虫将作为使用长读长序列进行深度测序的遗传物质来源。 测序与短读方法一起产生高度连续的基因组组装。研究 在这个应用中提出的是创新的，因为我们将开发一种实验上易于处理的天然宿主 具有良好描述的生理学和生物化学的模型，使其成为人类的优秀转化模型 钩虫此外，自然进化的多重耐药A。犬已经存在， 容易获得，提供源遗传材料来询问与抗性有关的遗传位点。 人类钩虫目前还没有类似的生物资源和利用它们进行发现的模型。 拟议的研究是重要的，因为它有望提供必要的资源，并改善 在很大程度上研究耐药性和其他重要性状的生物学和遗传学的技术能力 被忽视但与医学相关的病原体最终，这项研究中创造的资源将促进未来的发展。 调查，以开发必要的研究和诊断工具，支持和维持全球方案， 消灭人类钩虫是一个公共卫生问题。预计这些成果将产生积极的影响。 通过提高可持续性， MDA策略，使其有可能消除STH疾病，同时最大限度地减少长期 由于驱虫药耐药性导致程序失败。