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佳，并且保持高度分散，使得无法 确定响应药物治疗的遗传结构的变化，从而确定相关的基因 具有耐药性。长期目标是直接为全球健康策略提供缓解和解决的信息 使用临床应用和遗传/基因组的土壤传播的蠕虫（STH）寄生虫中的耐药性 方法。该应用程序的总体目的是开发用于维持全球计划的研究工具 消除人钩虫是公共卫生问题。这项研究的理由是发展 最佳动物模型并产生高度连续的钩虫基因组组件，将允许 识别阻力基因座和开发新诊断以支持和维持全球大众药物 行政计划（MDA）。我们提出了两个具体目标：1）开发一种新型的犬种模型来支持 对钩虫生物学和遗传学的研究以及2）为A产生高度连续的基因组组装。 caninum。在第一个目的中，将进行A. caninum钩虫的单对单位垫子的新型系统将是 开发，将一对雄性/女性未成熟的蠕虫放在明胶胶囊中，该囊将被沉积 通过内窥镜指导递送在jejunum中期。线虫中高水平的多态性限制了连续性 基因组组件，因此我们将使用该模型产生新的近交系，并具有降低的多态性。为了 第二个目的，近交蠕虫将作为使用长阅读的深层测序的遗传材料来源 与短阅读方法一起进行测序，以产​​生高度连续的基因组组装。研究 在此应用程序中提出的是创新的 具有很好描述的生理学和生物化学的模型，使其成为人类的出色翻译模型 钩虫。此外，天然进化的抗an的多药耐药分离株已经存在，并且是 随时可用，提供源遗传物质来询问与抗性有关的遗传基因座。 类似的生物资源和用于发现发现的模型对于人钩虫目前不存在。 拟议的研究很重要，因为它有望提供基本资源并改善 在很大程度上研究耐药性和其他重要特征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 调查以开发支持和维持全球计划所需的研究和诊断工具 消除人钩虫是公共卫生问题。这些结果预计会有积极的 通过改善可持续性，对生活在钩虫流行地区的人的健康和福祉的影响 MDA策略，使既可以从STH中消除疾病，同时最大程度地减少长期的风险 由于驱虫阻力引起的程序故障。