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: 10544786
• 负责人: Rachel Fath Daniels
• 金额: $ 19.99万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544786
• 关键词: Address; Ancylostoma caninum; Animal Model; Animals; Anthelmintics; Biochemistry; Biological; Biological Models; Biology; Candidate Disease Gene; Canis familiaris; Chromosome Mapping; Clinical; Communicable Diseases; Communities; DNA Resequencing; Deposition; Development; Disease; Drug resistance; Economic Burden; Endoscopy; Failure; Female; Future; Gelatin; Genes; Genetic; Genetic Materials; Genetic Polymorphism; Genetic Variation; Genome; Genomic approach; Genomics; Ghana; Goals; Haemonchus; Haiti; Health; Helminths; High-Throughput Nucleotide Sequencing; Hookworms; Human; Inbreeding; Investigation; Medical; Mission; Modeling; Multi-Drug Resistance; Necator americanus; Nematoda; Outcome; Parasites; Parasitic nematode; Partner in relationship; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiology; Public Health; Recording of previous events; Reporting; Research; Resistance; Resistance development; Resources; Sampling; Sheep; Single Nucleotide Polymorphism; Soil; Source; System; United States National Institutes of Health; Variant; Work; benzimidazole; benzimidazole resistance; beta Tubulin; burden of illness; canine model; capsule; deep sequencing; diagnostic tool; disability; genetic architecture; genome resource; genome sequencing; genomic locus; global health; improved; innovation; jejunum; male; molecular diagnostics; neglect; novel; novel diagnostics; pathogen; prevent; programs; resistance gene; response; risk minimization; tool; trait; translational model; transmission process; whole genome

PROJECT SUMMARY/ABSTRACT 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.

项目概要/摘要 目前钩虫基因组的组装很差并且仍然高度碎片化，因此不可能 确定响应药物治疗的遗传结构的变化，从而识别相关基因 具有耐药性。长期目标是直接为全球卫生战略提供信息，以缓解和解决问题 利用临床应用和遗传/基因组研究土源性蠕虫 (STH) 寄生虫的耐药性 接近。该应用程序的总体目标是开发研究工具来维持全球项目 消除作为公共卫生问题的人类钩虫。这项研究的基本原理是，开发 最佳动物模型和产生钩虫高度连续的基因组组装将允许 识别耐药位点并开发新的诊断方法以支持和维持全球大规模药物 管理计划（MDA）。我们提出两个具体目标：1）开发一种新颖的犬类模型来支持 对钩虫生物学和遗传学的研究，以及 2) 为钩虫产生高度连续的基因组组装。 犬科动物。第一个目标是开发一种用于犬钩虫单对交配的新系统 将一对雄性/雌性未成熟蠕虫放入明胶胶囊中并沉积 通过内窥镜引导输送在空肠中部。线虫的高水平多态性限制了邻近性 基因组组装，因此我们将使用该模型来产生多态性减少的新自交系。为了 第二个目标，近交蠕虫将作为使用长读长进行深度测序的遗传物质来源 测序与短读长方法一起产生高度连续的基因组组装。研究 本申请中提出的方案具有创新性，因为我们将开发一种实验上易于处理的天然宿主 模型具有详细的生理学和生物化学描述，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犬放线菌分离株已经存在并且正在研究中。 容易获得，提供源遗传物质来询问与抗性有关的遗传位点。 对于人类钩虫来说，目前还不存在类似的生物资源和利用它们进行发现的模型。 拟议的研究意义重大，因为预计它将提供必要的资源并改善 研究耐药性的生物学和遗传学以及其他重要特征的技术能力 被忽视但医学上相关的病原体。最终，本研究中创建的资源将促进未来 进行调查以开发支持和维持全球计划所需的研究和诊断工具 消除作为公共卫生问题的人类钩虫。预计这些成果将产生积极影响 通过提高可持续性对生活在钩虫流行地区的人们的健康和福祉产生影响 MDA 策略，可以消除 STH 带来的疾病，同时最大限度地降低长期风险 由于驱虫药耐药性而导致程序失败。