Overcoming multidrug-resistance in hookworms

克服钩虫的多重耐药性

基本信息

批准号：
10453163
负责人：
Matthew Brewer
金额：
$ 19.13万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-16 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453163
关键词：
ABCB1 gene Accounting Address Adult Amino Acids Ancylostoma (genus)Ancylostoma caninum Anthelmintics Binding Binding Sites Biological Assay CRISPR/Cas technology Canis familiaris Communicable Diseases Cutaneous Drug Targeting Drug or chemical Tissue Distribution Drug resistance Exhibits Future Genes Glycoproteins Goals Hookworms Human Kinetics Knowledge Larva Larva Migrans Life Cycle Stages Mammals Maps Measures Mediating Messenger RNA Mission Modeling Multi-Drug Resistance Nematoda Orthologous Gene Outcome Parasite resistance Parasites Permeability Persons Pharmaceutical Preparations Pharmacology Pharmacotherapy Property Resistance Site System Techniques Testing Tissues United States United States National Institutes of Health Veterinarians Zoonoses disability-adjusted life years enteritis human disease in vivo inhibitor lactogenesis novel prevent receptor response transmission process

项目摘要

Project Summary Ancylostoma caninum causes cutaneous larva migrans and eosinophilic enteritis in humans. The reason these human diseases cannot be eliminated is because the parasite persists in the canine reservoir host. Multi-drug resistant isolates of A. caninum are now circulating in the United States. In addition, specific life cycle stages (tissue- dwelling larvae) are tolerant of anthelmintics even when the isolate is considered “drug susceptible.” Our hypothesis is that A. caninum evades drug treatment with permeability glycoproteins (P-glycoproteins) that efflux anthelmintics and prevent them from binding target receptors. In this application we propose to 1) identify the spectrum of anthelmintics enhanced by P-glycoprotein inhibition in A. caninum, 2) record the repertoire of Pgps expressed in response to each drug class, 3) map the precise tissues where Pgps are expressed, 4) characterize the pharmacological profile of Aca-Pgp-11, and 5) empirically determine regions of specific sites of nematode P-glycoprotein that could be exploited. Our results will inform future studies testing the hypothesis that nematode-specific P-glycoprotein inhibitors can be used to restore efficacy of multiple existing anthelmintics and overcome drug resistant Ancylostoma.

项目概要犬钩虫引起皮肤幼虫移行症和嗜酸性粒细胞性肠炎人类之所以无法消除这些人类疾病，是因为寄生虫持续存在于犬类宿主体内，具有多重耐药性的犬曲霉分离株。现在在美国流通。此外，特定的生命周期阶段（组织- 即使分离株被认为是“药物”，居住幼虫也能耐受驱虫药。易感性。” 我们的假设是，A. caninum 通过渗透性逃避药物治疗糖蛋白（P-糖蛋白）流出驱虫剂并防止它们结合在此应用中，我们建议 1) 确定目标受体的谱。通过 A. caninum 中的 P-糖蛋白抑制增强驱虫药，2) 记录针对每种药物类别表达的 Pgps 库，3) 绘制精确的组织图其中 Pgps 被表达，4) 表征 Aca-Pgp-11 的药理学特征， 5)凭经验确定线虫P-糖蛋白特定位点的区域我们的结果将为未来测试这一假设的研究提供信息。线虫特异性 P-糖蛋白抑制剂可用于恢复多种药物的功效现有驱虫药并克服耐药性钩虫。