Oxygen sensation in human-parasitic skin-penetrating nematodes

人体寄生皮肤穿透线虫的氧感觉

• 批准号: 10750771
• 负责人: Breanna M. Walsh
• 金额: $ 4.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750771
• 关键词: Adult; Afferent Neurons; Ancylostoma (genus); Anthelmintics; Atmosphere; Behavior; Behavioral; Behavioral Assay; Biology; CRISPR/Cas technology; Caenorhabditis elegans; Calcium; Carbon Dioxide; Clinical Management; Communicable Diseases; Communities; Coughing; Cues; Data; Dedications; Deglutition; Development; Disease; Drosophila melanogaster; Ectopic Expression; Enterobius; Environment; Esthesia; Etiology; Excretory function; Exhibits; Exposure to; Feces; Female; Gastrointestinal tract structure; Genetic; Genetic Transcription; Goals; Helminths; Hookworms; Human; Image; Imaging Techniques; Immunocompromised Host; In Vitro; Individual; Indolent; Infrastructure; Intervention; Intestines; Invertebrates; Laboratory Study; Larva; Life; Life Cycle Stages; Lung; Measures; Mediating; Medical; Mentorship; Modeling; Molecular; Molecular Biology; Molecular Target; Morbidity - disease rate; Movement; Mutagenesis; Necator; Nematoda; Nematode infections; Neuroanatomy; Neurobiology; Neurons; Neurosciences; Neurosciences Research; Oxygen; Parasites; Parasitic nematode; Parasitology; Pathway interactions; Penetration; Persons; Physicians; Population; Predisposition; Process; Proliferating; Property; Protein Sequence Homologs; Reporter; Resistance; Resource-limited setting; Role; Sanitation; Scientist; Sensory; Signal Transduction; Skin; Soil; Soluble Guanylate Cyclase; Strongyloides stercoralis; Strongyloidiasis; Surface; Syndrome; System; Techniques; Temperature; Testing; Therapeutic; Therapeutic Intervention; Training; Trees; Work; behavioral response; burden of illness; cell motility; design; egg; gastrointestinal; gastrointestinal infection; hatching; high risk; immunosuppressed; insight; interest; intestinal villi; mortality; neighborhood disadvantage; neural; novel; novel strategies; parasitism; prevent; respiratory; response; sensor; sensory mechanism; skills; therapeutic target; transmission process

PROJECT SUMMARY / ABSTRACT The goal of this proposal is to leverage molecular neuroscience techniques to define the role of oxygen (O2) as a biologically relevant chemosensory cue in the human-infective threadworm Strongyloides stercoralis. Globally, S. stercoralis infects ~610 million people, with a high disease burden in resource-poor settings. Strongyloidiasis, considered an emerging and/or re-emerging disease, can manifest as an indolent multi-decade gastrointestinal infection; immunocompromised individuals are at high risk of hyperinfection syndrome and disseminated disease – of which most cases are fatal. Given the threat of anthelmintic resistance, novel chemotherapeutic strategies are needed to treat and cure individuals with strongyloidiasis. Parasitic nematodes rely upon neuronally detected sensory cues to actively seek hosts, navigate intra- and extra-host environments, and coordinate their development with their local context. S. stercoralis, as a soil- transmitted helminth, thrives in O2 concentrations that range from atmospheric levels (~21%) at the soil surface to near-anaerobic conditions in the host intestinal tract. However, O2 sensation remains completely unstudied in S. stercoralis or any other parasitic nematode. This proposal hypothesizes that the neural and molecular machinery mediating O2 sensation in S. stercoralis may yield promising targets vulnerable to intervention. This proposal will explore O2 sensation in S. stercoralis at the behavioral, neuronal, and molecular levels. The first aim of this proposal seeks to characterize how O2 serves as a chemosensory cue to sculpt the motile behaviors of S. stercoralis throughout its parasitic life cycle. Quantitative analysis of parasite behaviors in different O2 contexts will be performed. Additionally, work proposed in the first aim will interrogate the role of shifting O2 levels as a developmental cue that enables parasitism. In the second aim of this proposal, chemogenetic neuronal silencing and calcium imaging techniques will be employed to both identify O2-sensing neurons and describe parasite-specific encoding properties in these neurons. In the proposal’s third aim, CRISPR/Cas9-mediated mutagenesis and ectopic expression systems will be used to determine the molecular sensors of O2 in S. stercoralis and explore their mechanism of action. This proposal will generate new insights into parasite chemosensory neurobiology and may reveal novel strategies for preventing nematode infections. This proposal will support the applicant’s goal of becoming a physician-scientist dedicated to the study and clinical management of parasitic infectious diseases. In completing the proposed aims, the applicant will augment prior training in parasitology and molecular biology with the development of new skills in neuroscience research. This work will be performed in one of the only laboratories studying neurobiology in parasitic nematodes; the applicant will also seek mentorship from the rich community of parasitologists and neuroscientists at UCLA.

项目摘要/摘要 这项提议的目标是利用分子神经科学技术来确定氧(O2)的作用。 作为人类感染线虫的生物相关的化学感官线索。 在全球范围内，粪链球菌感染了约6.1亿人，在资源匮乏的环境中，疾病负担很高。 管圆线虫病被认为是一种新出现的和/或再次出现的疾病，可表现为数十年的惰性 胃肠道感染；免疫功能低下的人患上高度感染综合症的风险很高 播散性疾病--其中大多数病例是致命的。考虑到驱虫剂耐药性的威胁，小说 需要化疗策略来治疗和治愈患有弓形虫病的人。 寄生线虫依靠神经检测到的感觉线索来主动寻找宿主，在体内和 外部宿主环境，并将其发展与当地环境相协调。作为一种土壤- 传播的蠕虫，在土壤表面大气水平(~21%)的O2浓度范围内繁衍生息 在宿主肠道中处于接近厌氧的状态。然而，氧气的感觉仍然完全没有被研究过 或任何其他寄生线虫。这一提议假设神经和分子 在司氏杆菌中调节O2感觉的机制可能产生容易受到干预的有希望的靶点。 这项提议将在行为、神经元和分子水平上探索粪便螺菌对O2的感觉。这个 这项提议的第一个目标是描述氧气如何作为化学感官线索来塑造运动性的 龟纹夜蛾在寄生生活史中的行为黄海地区寄生虫行为的定量分析 将执行不同的O2上下文。此外，第一个目标中提出的工作将审问 氧气水平的变化是导致寄生的发育线索。在这项提案的第二个目标中， 化学发生神经元沉默和钙成像技术将被用来识别O2-感觉 并描述了这些神经元中寄生虫特有的编码特性。在提案的第三个目标中， CRISPR/Cas9介导的突变和异位表达系统将用于确定分子 并探讨其作用机制。这项建议将产生新的见解 研究寄生虫的化学感觉神经生物学，并可能揭示预防线虫感染的新策略。 这项提案将支持申请者成为一名致力于这项研究的内科科学家的目标，并 寄生虫病的临床管理。在完成建议的目标时，申请者将增加 随着神经科学研究新技能的发展，在寄生虫学和分子生物学方面的先前培训。 这项工作将在仅有的研究寄生线虫神经生物学的实验室之一进行； 申请者还将寻求加州大学洛杉矶分校寄生虫学家和神经学家组成的富有社区的指导。