Pharmacological Diversity of nAChRs in Clade III Nematodes: Levamisole receptors

进化枝 III 线虫中 nAChR 的药理学多样性：左旋咪唑受体

基本信息

批准号：
8501957
负责人：
Richard John Martin
金额：
$ 35.08万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501957
关键词：
Adult Affect Agonist Animals Anthelmintics Ascariasis Ascaris Ascaris lumbricoides Ascaris suum Biological Assay Brugia Brugia malayi Caenorhabditis elegans China Cloning Complex Country Development Disease Dose Drosophila acetylcholine receptor alpha-subunit Drug Combinations Drug Controls Drug effect disorder Elephantiasis Figs - dietary Filarial Elephantiases Future Human Intestines Investigation Ion Channel Knowledge Lactones Larva Lead Levamisole Methods Molecular Muscle Muscle Contraction Nematoda Nicotinic Receptors Outcome Parasites Parasitic Diseases Parasitic nematode Pharmaceutical Preparations Pharmacology Preparation Prevention Property Refractory Research Research Personnel Resistance Resistance development Site Surgical Flaps System Testing Therapeutic Therapeutic Effect Toxin Tropical Disease Vaccines Variant Xenopus oocyte avermectin channel blockers chemotherapy cholinergic drug development filaria improved innovation levamisole resistance neglect novel patch clamp public health relevance receptor response stoichiometry synergism transmission process voltage clamp voltage/patch clamp

项目摘要

DESCRIPTION (provided by applicant): 1. The Neglected Tropical Diseases include ascariasis and lymphatic filariasis. These diseases are caused by parasitic nematodes that are grouped in Clade III because of their molecular similarities. Ascariasis is caused by the large intestinal roundworm, Ascaris lumbricoides. Worldwide, it occurs in 1.4 billion people. Lymphatic filariasis (elephantiasis) threatens over a billion people in 83 countries; it is caused by filaria nematodes like Brugia malayi. Control of these nematode parasites (adults or larvae) relies on a limited number of anthelmintic drugs. There are concerns that mass chemotherapy will lead to the development of resistance. There is a significant and urgent need for research that will allow better use of existing drugs, including combinations, to preserve their value, and to develop new drugs. 2. Recently, several novel nematode selective cholinergic anthelmintics, like tribendimidine and derquantel (now synergized with abamectin), have been introduced and increased the significance of cholinergic anthelmintics. Tribendimidine has potential for single-dose Mass Drug Administration. Derquantel has 'resistance busting' actions against worms that are resistant to other cholinergic anthelmintics. The pharmacology of nematode nicotinic receptors (nAChRs) is more complex than has been appreciated. The muscle nAChRs are divided into N-, L- and B-subtypes in the Clade III nematode Ascaris suum. The pharmacology of Clade III muscle receptors (levamisole receptors) are modulated by receptor subunit composition. The therapeutic importance of subtypes and modulation demands further investigation in parasitic nematodes. We have three aims. 3. Our approach will use muscle contraction assays, current-clamp, voltage-clamp, patch- clamp, cloning & Xenopus oocyte expression and pharmacological agents, to characterize actions of cholinergic anthelmintics and the subtypes of their receptors. Aim #1 will characterize the mode of action and subtype selectivity of tribendimidine in A. suum. It will test the hypothesis that tribendimidine is not selective for the L-subtype of nAChR but another type in A. suum and determine if its action as an open-channel blocker limits efficacy. Aim #2 will examine the effects of subunit arrangements and stoichiometry on pharmacology of Ascaris nAChRs. It will express four specific nicotinic receptor subunits from A. suum in different combinations to test the hypothesis that different subunit compositions reproduce the pharmacological diversity of native muscle receptors (levamisole receptors). Aim #3 will characterize nAChR responses and receptors in B. malayi, to test the hypothesis that the subtypes are functionally similar to the Clade III nematode, A. suum. 4. The proposal is innovative, exploring unknown drug effects and effects of subunit arrangements on the pharmacological properties of Clade III nAChRs. We also extend, to the Brugia malayi parasite preparation, the methods that this group of investigators has developed. 5. The overall impact will be a powerful influence on: expansion & informed use of tribendimidine, a potential single-dose MDA; the expansion and informed use of the pharmacological diversity of nicotinic anthelmintic target sites in Clade III nematodes; use of a novel B. malayi preparation for studying ion-channel targets for future drug development; development or informed use of combinations (e.g. derquantel with avermectins; or combinations of subtype selective cholinergic anthelmintics).

描述（由申请人提供）：1。被忽视的热带疾病包括粘液症和淋巴丝虫病。这些疾病是由寄生线虫由于分子相似性而在进化枝III中分组的。 as虫病是由大肠round虫，阿斯卡里斯lumbricoides引起的。在全球范围内，它发生在14亿人中。在83个国家 /地区，淋巴丝虫病（象症）威胁着十亿人口；它是由像布鲁吉亚·马来（Brugia Malayi）这样的丝状线虫引起的。这些线虫寄生虫（成人或幼虫）的控制取决于有限数量的驱虫药物。人们担心质量化疗将导致抗药性的发展。迫切需要进行研究，可以更好地利用现有药物，包括组合，以保持其价值并开发新药。 2。最近，已经引入了几种新型的线虫选择性胆碱能驱虫药，例如Tibendimidine和derquantel（现已与Abamectin协同作用），并提高了胆碱能驱虫药的重要性。 tirendimidine具有单剂量大量药物给药的潜力。 DerQuantel对对其他胆碱能驱虫药具有抗性的蠕虫具有“阻力破坏”的作用。线虫烟碱受体（NACHR）的药理学比所欣赏的更为复杂。肌肉NACHR被分为nematode asscaris suum中的n-，l-和b-subtypes。进化枝III肌肉受体（Levamisole受体）的药理学通过受体亚基组成调节。亚型和调节的治疗重要性需要在寄生线虫中进一步研究。我们有三个目标。 3。我们的方法将使用肌肉收缩分析，电流钳，电压夹，斑块夹，克隆和爪蟾卵母细胞表达和药理学剂来表征胆碱能驱虫药及其受体亚型的作用。 AIM＃1将表征A. suum中tibendimidine的作用方式和亚型的选择性。它将检验以下假设：tirendimidine对NACHR的L-辅助类型不是选择性的，而是A. suum中的另一种类型，并确定其作用是否作为开放通道阻滞剂限制了功效。 AIM＃2将检查亚基排列和化学计量对Ascaris NACHRS药理学的影响。它将在不同组合中表达四个特定的烟碱受体亚基，以检验以下假设：不同的亚基组成再现了天然肌肉受体（levamisole受体）的药理多样性。 AIM＃3将表征Malayi B. Malayi中的NACHR反应和受体，以检验以下假设：亚型在功能上与进化枝III线虫A. suum相似。 4。该提案是创新的，探讨了亚基排列对进化枝III NACHRS药理特性的未知作用和影响。我们还扩展到Brugia Malayi寄生虫的制备，这组研究人员已经开发了这种方法。 5。总体影响将是对：扩展和知情的Tibendimidine，一种潜在的单剂量MDA；进化枝III线虫中烟碱驱虫目标位点的药理多样性的扩展和知情使用；使用新颖的马来语准备工作来研究未来药物开发的离子通道靶标；组合的开发或知情使用（例如，与平均毒素的德夸氏素；或亚型选择性胆碱能驱虫药的组合）。