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Oxygen sensation in human-parasitic skin-penetrating nematodes

人体寄生皮肤穿透线虫的氧感觉

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案的目标是利用分子神经科学技术来定义氧气 (O2) 的作用作为人类感染性线虫粪类圆线虫的生物相关化学感应线索。在全球范围内，粪圆线虫感染了约 6.1 亿人，在资源匮乏的地区造成了很高的疾病负担。类圆线虫病被认为是一种新出现和/或重新出现的疾病，可表现为几十年来的惰性疾病胃肠道感染；免疫功能低下的个体患过度感染综合征的风险很高，传播性疾病——其中大多数病例是致命的。鉴于驱虫药耐药性的威胁，新颖需要化疗策略来治疗和治愈类圆线虫病患者。寄生线虫依靠神经元检测到的感觉线索来主动寻找宿主、在体内和体内导航。宿主外环境，并根据本地环境协调其开发。 S. stercoralis，作为土壤传播的蠕虫，在土壤表面的 O2 浓度范围为大气水平 (~21%) 的情况下会大量繁殖宿主肠道中的近厌氧条件。然而，O2 感觉仍然完全未被研究过。粪圆线虫或任何其他寄生线虫。该提议假设神经和分子粪圆线虫介导 O2 感觉的机制可能会产生易于干预的有希望的目标。该提案将在行为、神经元和分子水平上探索粪圆线虫的 O2 感觉。这该提案的第一个目标是描述 O2 如何作为化学感应线索来塑造运动粪圆线虫在其整个寄生生命周期中的行为。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质疑改变 O2 水平作为实现寄生的发育线索。在该提案的第二个目标中，化学遗传学神经元沉默和钙成像技术将用于识别 O2 感应神经元并描述这些神经元中寄生虫特异性的编码特性。在该提案的第三个目标中， CRISPR/Cas9介导的诱变和异位表达系统将用于确定分子粪圆线虫中的 O2 传感器并探讨其作用机制。该提案将产生新的见解研究寄生虫化学感应神经生物学，并可能揭示预防线虫感染的新策略。该提案将支持申请人成为一名致力于研究和研究的医师科学家的目标寄生虫感染性疾病的临床治疗。在完成拟议的目标时，申请人将增强先前接受过寄生虫学和分子生物学培训，并发展了神经科学研究的新技能。这项工作将在唯一研究寄生线虫神经生物学的实验室之一进行；这申请人还将向加州大学洛杉矶分校丰富的寄生虫学家和神经科学家群体寻求指导。