Neurophysiological and Neuropharmacological Studies of a Parasitic Nematode

描述(申请人提供)：寄生线虫作为疾病的主要贡献者困扰着世界，而抗寄生虫药物(驱虫药)是主要的控制措施。需要新的化疗药物或改进目前使用的药物，因为寄生虫继续对当前的药物产生抗药性。新驱虫剂的发现和/或验证以及对目前使用的药物的改进需要彻底了解这些驱虫剂的功效、它们的具体目标和作用机制。大多数驱虫剂以运动系统为靶标，直接或间接地损害线虫移动和停留在宿主中的能力。以前的工作主要集中在驱虫对线虫肌肉的影响上。不幸的是，人们对驱虫剂或潜在驱虫剂对神经系统(控制运动行为)的影响知之甚少，因为研究线虫神经细胞的神经生理学极其困难。这项拟议的研究将利用我的实验室直接记录线虫神经元的能力，并将使用电生理和神经药理学技术。总的目标是确定有希望的新药物的神经元靶点和作用机制，最终可能添加到我们的化疗武器库中，以及更深入地探索两种非常广泛使用的驱虫药的可能靶点和作用机制。利用猪蛔虫寄生线虫，我们将评估以下药物：PF1022A、硝唑尼特及其代谢物替奥沙尼特、蛙黄素、两种阿片类生物碱、对甲氧喹胺、伊维菌素和阿苯达唑。将研究的神经生理反应包括：自发和诱发的电活动变化，神经元信号能力的变化，以及对突触传递到肌肉和运动回路中其他神经元的影响。 相关性：拟议的研究将有助于描绘或提炼抗寄生虫剂、它们在线虫神经系统中的靶标和作用机制。这项工作是由一种假设驱动的，即被研究的药物损害了寄生虫的神经肌肉系统的功能；初步证据支持这一假设，即被研究的药物。这项工作是基础研究和转化研究的结合，将进一步推动我们开发有效的抗寄生虫药物。

DESCRIPTION (provided by applicant): Parasitic nematodes plague the world as major contributors to disease, and anti-parasitic drugs (anthelmintics) are the primary control measure. New chemotherapeutic agents or improvements in currently used agents are needed because parasitic helminths continue to develop resistance against current medications. Discovery and/or validation of new anthelmintic agents as well as improvement of currently used drugs require a thorough understanding of the efficacy of these agents, their specific targets and mechanisms of action. Most anthelmintics target the locomotory system and either directly or indirectly compromise the ability of nematodes to move and remain in the host. Previous work has focused on anthelmintic effects on nematode muscle. Unfortunately, little is known about the effects of anthelmintics or potential anthelmintics on the nervous system (which controls locomotory behavior), because studying the neurophysiology of nematode nerve cells has been extremely difficult. The proposed research will make use of my lab's ability to directly record from nematode neurons and will use electro-physiological and neuropharmacological techniques. The overall goal is to determine neuronal targets and mechanisms of action for promising new agents that might ultimately be added to our chemotherapeutic arsenal as well as to explore in more depth the possible targets and mechanisms of action of two very widely used anthelmintics. Using the parasitic nematode Ascaris suum, we will assess the following agents: PF1022A, nitazoxanide and its metabolite tizoxanide, bombesin, two opioid-related alkaloids, paraherquamide, ivermectin and albendazole. The neurophysiological responses that will be studied include: spontaneous and evoked changes in electrical activity, changes in neuronal signaling capabilities, and effects on synaptic transmission to muscles and other neurons in the locomotory circuit. RELEVANCE: The proposed research will help to delineate or refine anti-parasitic agents, their targets and mechanisms of action in the nematode nervous system. This work is driven by the hypothesis that the agents to be studied compromise the function of the parasite's neuromuscular system; preliminary evidence supports this hypothesis for the agents to be studied. This work is a combination of basic and translational research which will further our efforts to develop effective anti-parasitic medications.