Cholinergic receptors on the nematode pharynx: an unexploited drug target

线虫咽部的胆碱能受体：一个未开发的药物靶点

• 批准号: 8303109
• 负责人: Alan P Robertson
• 金额: $ 18.28万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-17 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303109
• 关键词: Adult; Affect; Age; Animals; Anthelmintics; Ascariasis; Ascaris; Ascaris suum; Child; Cholinergic Receptors; Development; Disease; Drosophila acetylcholine receptor alpha-subunit; Drug Delivery Systems; Drug resistance; Drug usage; Genes; Goals; Growth; Helminthiasis; Hookworms; Hour; Human; Infant; Infection; Integral Membrane Protein; Intestines; Ion Channel; Lead; Levamisole; Libraries; Life; Methods; Muscle; Nematoda; Nicotinic Receptors; Oocytes; Paralysed; Parasite Control; Parasites; Parasitic infection; Parasitic nematode; Patch-Clamp Techniques; Pharmaceutical Preparations; Pharmacology; Pharyngeal structure; Population; Property; Protein Subunits; Pyrantel; Reporting; Research; Resistance; Resistance development; Screening procedure; Site; Soil; Testing; Trichuris; Trichuris trichiura infection; Tropical Disease; Veterinary Medicine; Work; Xenopus laevis; Xenopus oocyte; avermectin; chemotherapy; cholinergic; drug discovery; in vivo; interest; man; neglect; novel; novel therapeutic intervention; receptor; receptor function; reconstitution; response; spastic paralysis; voltage/patch clamp

DESCRIPTION (provided by applicant): The Neglected Tropical Diseases (NTDs) include the soil-transmitted helminthiases (STHs) which are caused by diverse groups of intestinal nematodes. The parasites include Ascaris, Trichuris and hookworms. These infections are common. Ascariasis for example, affects 1.4 billion people worldwide and is most common in children between the ages of 3 and 8. Control of these nematode parasites relies on an effective supply of anthelmintics. Taking veterinary medicine as an example, we know that continued use of anthelmintic compounds for mass chemotherapy will lead to drug resistance. There is a need to identify novel target sites for anthelmintic development. Once such site is the nicotinic acetylcholine receptor on the nematode pharynx. We have discovered this receptor does not respond to currently used anrthelmintic drugs. Approach: The specific aims of this application are: 1. Characterize nAChR responses in A. suum pharynx: using current-, voltage- & patch- clamp techniques. We will test the hypothesis that the A. suum pharynx nAChRs are pharmacologically distinct from the muscle nAChRs activated by cholinergic anthelmintics. 2. Identify & clone pharyngeal specific nicotinic acetylcholine receptor subunits. We will identify the nAChR subunit genes present in the pharynx required to produce functional receptors. 3. Characterize the pharyngeal cholinergic receptors in Xenopus laevis oocytes using voltage- & patch-clamp techniques. We will test the hypothesis that expression of pharyngeal nAChR subunits results in functioning receptors that are pharmacologically similar to those found in vivo. On completion of this project we will have characterized the pharmacology of an important new potential drug target in a parasitic nematode. We will have identified the genes that encode these receptors. Finally, we will have reconstituted the receptors in an accessible platform suitable for screening potential new anthelmintics. The longer term goal of this research is provide ion- channel drug targets from a range of important parasite species in a platform (Xenopus oocytes) suitable for drug discovery screening.

描述（由申请人提供）：被忽视的热带病（NTD）包括由不同肠道线虫引起的土壤传播蠕虫病（STH）。寄生虫包括蛔虫、鞭虫和钩虫。这些感染很常见。例如，蛔虫病影响全世界14亿人，在3至8岁的儿童中最常见。控制这些线虫寄生虫依赖于有效供应驱虫剂。以兽药为例，我们知道继续使用驱虫化合物进行大规模化疗会导致耐药性。需要鉴定用于驱虫剂开发的新靶位点。一旦这样的网站是烟碱乙酰胆碱受体的线虫咽。我们已经发现这种受体对目前使用的驱虫药没有反应。方法：本申请的具体目的是：1。表征A中的nAChR反应。咽部：采用电流钳、电压钳和膜片钳技术。我们将检验A.猪咽nAChR与胆碱能驱虫剂激活的肌肉nAChR截然不同。2.咽部特异性烟碱乙酰胆碱受体亚单位的鉴定与克隆。我们将确定nAChR亚基基因存在于咽部产生功能性受体所需的。3.应用电压钳和膜片钳技术研究非洲爪蟾卵母细胞咽部胆碱能受体。我们将检验这样的假设：咽部nAChR亚基的表达会产生与体内发现的受体在药理学上相似的功能受体。在这个项目完成后，我们将在寄生线虫中描述一个重要的新的潜在药物靶点的药理学特征。我们将已经确定了编码这些受体的基因。最后，我们将在一个可访问的平台上重建受体，适合筛选潜在的新驱虫剂。本研究的长期目标是在适合药物发现筛选的平台（非洲爪蟾卵母细胞）中提供来自一系列重要寄生虫物种的离子通道药物靶点。