Schistosome TRP ion channels as potential drug targets

描述(申请人提供)：血吸虫，血吸虫属的寄生扁虫，引起血吸虫病，这是一种影响全球数亿人的热带疾病。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以买到的药物。这种情况是危险的，特别是考虑到有报道称寄生虫对吡喹酮产生了抗药性。因此，迫切需要新的治疗方法。目前大多数驱虫药以离子通道为靶点，证实这些蛋白质是杰出的治疗靶点。这个高风险、高回报的项目将启动对一类完全未知的血吸虫离子通道的研究，即瞬时受体电位(Trp)通道。Trp通道家族的成员在激活机制和离子选择性方面有着惊人的不同，但拥有共同的核心结构。它们对传递感觉信号、对广泛的外界刺激作出反应至关重要，也参与调节细胞内钙离子的水平。哺乳动物的色氨酸通道目前正在被作为治疗疼痛、癌症和其他各种疾病的治疗靶点进行深入的研究。我们假设，血吸虫Trp通道是完成血吸虫生命周期所必需的，该生命周期依赖于外部线索来寻找宿主并迁移到宿主内的偏好位置，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没有被探索。该项目将使用并行策略来确定这些通道在血吸虫生理学中所起的作用，并有可能为新的抗血吸虫药物提供新的靶点。其具体目的是：1.确定正常Trp通道功能的遗传和药理学干扰对血吸虫存活和生理的影响；2.从功能上表达和确定曼氏血吸虫Trp通道的一个子集的性质和药理敏感性。 公共卫生相关性：血吸虫病是一种影响全球数亿人的主要热带疾病。它是由被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，这是一个非常危险的情况。 显然，需要新的抗血吸虫病药物。许多治疗寄生虫感染的药物都针对离子通道，离子通道对寄生虫的神经肌肉系统的正常功能至关重要。因此，离子通道是新驱虫药潜在靶点的极佳选择。这个探索性项目将使用多种方法来研究一类以前从未被研究过的血吸虫离子通道，目的是确定它们在寄生虫生命周期中扮演的角色，以及干扰它们功能的方式。这些研究最终可能导致针对血吸虫病的新治疗策略。

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.