Schistosome TRP ion channels as potential drug targets

血吸虫 TRP 离子通道作为潜在的药物靶点

• 批准号: 8391914
• 负责人: ROBERT M GREENBERG
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391914
• 关键词: Adult; Affect; Anthelmintics; Antischistosomal Agents; Behavior; Calcium; Cations; Cell membrane; Cues; Development; Diffusion; Drug Delivery Systems; Family; Future; Genes; Genetic; Goals; Health; Helminths; Human; Investigation; Ion Channel; Ions; Lead; Life Cycle Stages; Light; Malaria; Mediating; Molecular; Molecular Genetics; Parasite resistance; Parasites; Parasitic Diseases; Pharmaceutical Preparations; Physiological; Physiology; Platyhelminths; Play; Praziquantel; Praziquantel resistance; Property; Proteins; Publishing; RNA Interference; Regulation; Reporting; Role; Schistosoma; Schistosoma mansoni; Schistosomatidae; Schistosomiasis; Sensory; Signal Transduction; Site; Stimulus; Structure; System; Testing; Therapeutic; Tissues; Toxin; Tropical Disease; base; cancer pain; high risk; inhibitor/antagonist; insight; member; migration; new therapeutic target; novel; novel strategies; novel therapeutics; receptor; research study; therapeutic target

DESCRIPTION (provided by applicant): Blood flukes, parasitic flatworms of the genus Schistosoma, cause schistosomiasis, a tropical disease that affects hundreds of millions of people worldwide. The current drug of choice against schistosomiasis is praziquantel. Indeed, praziquantel is the only drug currently available in most parts of the world. Such a situation is perilous, particularly in light of reports of emerging parasite resistance to praziquantel. The nee for new therapeutics is therefore urgent. The majority of current anthelmintic drugs target ion channels, validating these proteins as outstanding therapeutic targets. This high-risk, high-payoff project will initiate studies on an entirely unexplored family of schistosome ion channels, the transient receptor potential (TRP) channels. Members of the TRP channel family are strikingly diverse in their activation mechanisms and ion selectivity, but share a common core structure. They are critical to transducing sensory signals, responding to a wide range of external stimuli, and are also involved in regulating levels of intracellular calcium. Mammalian TRP channels are currently under intense investigation as therapeutic targets for treatment of pain, cancer, and a variety of other conditions. We hypothesize that schistosome TRP channels are essential to fulfillment of the schistosome life cycle, which depends on external cues for host-finding and migration to predilection sites within the host, as well as regulation of intracellular calcium. However, the function of these channels in schistosomes and other parasites is entirely unexplored. This project will use parallel strategies to define the roles thee channels play in schistosome physiology, and has the potential to provide novel targets for new antischistosomal agents. The specific aims are to: 1. Determine the effects of genetic and pharmacological disruption of normal TRP channel function on schistosome survival and physiology, and 2. Functionally express and determine the properties and pharmacological sensitivities of a subset of S. mansoni TRP channels. PUBLIC HEALTH RELEVANCE: Schistosomiasis is a major tropical disease affecting hundreds of millions worldwide. It is caused by parasitic flatworms called schistosomes. There is currently only a single drug generally used to treat schistosomiasis, a very treacherous situation. Clearly, new antischistosomal agents are needed. Many of the drugs against parasitic worm infestations target ion channels, which are essential to normal functioning of the parasite's neuromusculature. Thus, ion channels are an excellent choice as potential targets for new anthelmintic drugs. This exploratory project will use a variety of approaches to study a family of schistosome ion channels that have not previously been investigated, with the goal of defining the roles they play in the parasite life cycle and ways to interfere with their function. These studies could eventually lead to new therapeutic strategies against schistosomiasis.

描述（由申请人提供）：血吸虫是血吸虫属的寄生扁虫，会引起血吸虫病，这是一种影响全世界数亿人的热带疾病。目前治疗血吸虫病的首选药物是吡喹酮。事实上，吡喹酮是目前在世界大部分地区可用的唯一药物。这种情况是危险的，特别是考虑到寄生虫对吡喹酮产生抗药性的报道。因此，迫切需要新的治疗方法。目前大多数驱虫药都以离子通道为靶点，验证了这些蛋白质是出色的治疗靶点。这个高风险、高回报的项目将启动对一个完全未经探索的血吸虫离子通道家族——瞬时受体电位（TRP）通道的研究。 TRP 通道家族的成员在激活机制和离子选择性方面存在显着差异，但具有共同的核心结构。它们对于转导感觉信号、响应各种外部刺激至关重要，并且还参与调节细胞内钙的水平。哺乳动物 TRP 通道目前正在深入研究作为治疗疼痛、癌症和各种其他疾病的治疗靶点。我们假设血吸虫 TRP 通道对于血吸虫生命周期的完成至关重要，这取决于寻找宿主和迁移到宿主内偏好位点的外部线索，以及细胞内钙的调节。然而，这些通道在血吸虫和其他寄生虫中的功能完全未被探索。该项目将使用并行策略来定义这些通道在血吸虫生理学中发挥的作用，并有可能为新型抗血吸虫药物提供新的靶点。具体目标是： 1. 确定正常 TRP 通道功能的遗传和药理学破坏对血吸虫存活和生理学的影响，以及 2. 功能表达并确定曼氏血吸虫 TRP 通道子集的特性和药理学敏感性。 公共卫生相关性：血吸虫病是一种影响全世界数亿人的主要热带疾病。它是由称为血吸虫的寄生扁虫引起的。目前普遍用于治疗血吸虫病的药物只有一种，情况非常危险。 显然，需要新的抗血吸虫剂。许多对抗寄生虫感染的药物都针对离子通道，离子通道对于寄生虫神经肌肉系统的正常功能至关重要。因此，离子通道是新型驱虫药物潜在靶点的绝佳选择。该探索性项目将使用多种方法来研究以前未研究过的血吸虫离子通道家族，目的是确定它们在寄生虫生命周期中所扮演的角色以及干扰其功能的方法。这些研究最终可能导致针对血吸虫病的新治疗策略。