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.

项目摘要 ancylostoma caninum会导致皮肤幼虫和嗜酸性肠炎人类。这些人类疾病无法消除的原因是寄生虫持续存在于犬类储藏室中。 an的多药抗性分离株现在在美国流通。另外，特定的生命周期阶段（组织 - 即使被认为是“药物” 易受影响的。” 我们的假设是，A. caninum逃避了渗透性的药物治疗排出驱虫药的糖蛋白（P-糖蛋白）并防止它们结合目标接收器。在此应用中，我们建议1）确定 p-糖蛋白抑制在A. caninum中增强的驱虫药，2）记录 PGP的曲目响应每个药物类别，3）绘制精度组织在表达PGP的情况下，4）表征ACA-PGP-11的药物剖面， 5）线虫P-糖蛋白的特定位点的经验确定区域可以探索。我们的结果将为未来的研究提供依据，以检验以下假设线虫特异性P-糖蛋白抑制剂可用于恢复多重效率现有的驱虫药并克服了抗药性抗抗原瘤。