Schistosome TRP ion channels as potential drug targets

描述（由申请人提供）： 血吸虫是血吸虫属的寄生扁虫，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，吡喹酮是目前世界上大多数地区唯一可用的药物。这种情况是危险的，特别是鉴于有报告说寄生虫对吡喹酮产生抗药性。因此迫切需要新治疗方法。目前大多数驱虫药物靶向离子通道，验证这些蛋白质作为优秀的治疗靶点。这个高风险、高回报的项目将启动对一个完全未开发的染色体离子通道家族的研究，即瞬时受体电位（TRP）通道。 TRP通道家族的成员在其激活机制和离子选择性方面惊人地不同，但共享共同的核心结构。它们对于传导感觉信号、响应广泛的外部刺激至关重要，并且还参与调节细胞内钙的水平。哺乳动物TRP通道目前正作为治疗疼痛、癌症和各种其他病症的治疗靶点进行深入研究。我们假设，TRP通道是必不可少的，以履行的TRP生命周期，这取决于外部线索的主机发现和迁移到主机内的偏好网站，以及调节细胞内钙离子。然而，这些通道在寄生虫体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染色体生理学中发挥的作用，并有可能为新的抗染色体药物提供新的靶点。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染色体存活和生理的影响，以及2.功能表达和确定的属性和药理学敏感性的一个子集的S。 mansoni TRP通道。

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.