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.

项目摘要/摘要 钩虫基因组目前组装得很差，并且仍然高度碎片化，因此不可能 确定药物治疗后遗传结构的变化，从而确定相关基因 有抗药性。长期目标是直接为全球卫生战略提供信息，以减轻和解决 土源性寄生虫耐药性的临床和遗传研究 接近了。这个应用程序的总体目标是开发研究工具，以支持全球计划 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 一种最佳的动物模型和产生高度连续的钩虫基因组组装将允许 确定耐药基因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目标：1)建立一种新的犬模型以支持 对钩虫生物学和遗传学的研究和2)产生了一个高度连续的基因组组装。 金色的。在第一个目标中，一种新的进行犬钩线虫单对交配的系统将是 一对雄性/雌性幼虫被放置在明胶胶囊中，该胶囊将被存放在明胶胶囊中 在空肠中段通过内窥镜引导分娩。线虫中高水平的多态限制了邻接性 因此，我们将使用这个模型来产生一个新的多态减少的自交系。为 第二个目标是，近亲交配的蠕虫将作为使用Long-Read进行深度测序的遗传物质来源 与短读方法一起测序，以产生高度连续的基因组组装。这项研究 在此应用程序中提出的建议是创新的，因为我们将开发一种实验上易驯化的自然宿主 具有良好的生理和生物化学描述的模型，使其成为人类优秀的翻译模型 钩虫。此外，自然进化的多药耐药犬弧菌分离株已经存在并正在 容易获得，为询问与抗性有关的遗传位点提供了来源遗传物质。 类似的生物资源和利用它们进行发现的模式目前还不存在于人类钩虫身上。 拟议的研究具有重要意义，因为它有望提供必要的资源并改善 在很大程度上研究抗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 调查以开发必要的研究和诊断工具，以支持和维持全球方案 消灭人类钩虫是一个公共卫生问题。预计这些结果将产生积极的影响 通过改善可持续性，对钩虫流行区居民的健康和福祉产生影响 丙二醛战略，使得有可能在消除STH疾病的同时最大限度地减少长期 由于对驱虫药产生抗药性而导致程序失败。