Physiological roles of schistosome TRP ion channels with atypical pharmacology

血吸虫属的寄生扁虫引起血吸虫病，这是一种热带疾病 影响着全世界数以亿计的人。没有疫苗，只有一种药物(吡喹酮) 可用于治疗和控制。许多驱虫药，可能包括吡喹酮，作用于离子通道， 对神经肌肉系统和其他组织的正常功能至关重要的膜蛋白复合体 纸巾。然而，很少有蠕虫离子通道家族被评估它们的性质和作用 在寄生虫生理学方面。一组被忽视的蠕虫离子通道是瞬时受体电位 (Trp)通道超家族。Trp通道家族的成员在其激活过程中具有广泛的多样性 机理和离子选择性，但共享一个共同的核心结构。它们对感官的传递至关重要 信号，对广泛的外部刺激作出反应，也参与其他功能，如 调节细胞内钙离子和细胞器离子的动态平衡和运输。TRP渠道也会响应 内源性因子，包括那些参与炎症信号传递的因子。我们已出版的和初步的 药理学和基因敲除研究表明，血吸虫Trp通道可以靶向影响 神经肌肉和感觉功能正常。更重要的是，它们似乎具有新的药理作用。 敏感度。具体地说，我们的结果与血吸虫TRPA通道(SmTRPA)具有at 至少一些哺乳动物TRPV1通道的药理敏感性，尤其值得注意的是 血吸虫基因组中没有TRPV通道。初步功能表达研究 支持这一观点。我们推测，在血吸虫中，SmTRPA发挥了缺失的一些作用 TRPV频道。我们还假设SmTRPA和其他血吸虫Trp通道调节 成功感染所需的关键寄生虫-宿主相互作用。该项目将使用并行策略来 明确SmTRPA和其他Trp通道在血吸虫生物学中的作用，包括寄生虫-宿主 相互作用，并直接评估SmTRPA通道功能。最后，我们假设血吸虫Trp 通道，SmTRPML，在血吸虫内溶体生理中发挥关键作用，可以影响自噬和 养料的获取。我们的研究将阐明几乎一个人的生物学作用和生理特性 完全未经探索的寄生虫离子通道家族，这些信息可能在未来被用来提供 新的候选抗血吸虫药物或改变其用途的目标。该项目的具体目标是： 1)确定SmTRPA和其他Trp通道在血吸虫生命周期中的作用，包括 2)利用功能表达检测血吸虫对TRPV1的敏感性 调节物是由SmTRPA特异性介导的；以及3)阐明血吸虫TRPML通道的作用 内溶体功能，包括营养获取和自噬。

Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a tropical disease affecting hundreds of millions of people worldwide. There is no vaccine, and only a single drug (praziquantel) available for treatment and control. Many anthelmintics, likely including praziquantel, act on ion channels, membrane protein complexes that are essential for normal functioning of the neuromusculature and other tissues. However, few helminth ion channel families have been assessed for their properties and for their roles in parasite physiology. One such overlooked group of helminth ion channels is the transient receptor potential (TRP) channel superfamily. Members of the TRP channel family are widely 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 other functions, such as regulating intracellular calcium and organellar ion homeostasis and trafficking. TRP channels also respond to endogenous agents, including those involved in inflammatory signaling. Our published and preliminary pharmacological and knockdown studies show that schistosome TRP channels can be targeted to impact normal neuromuscular and sensory function. More significantly, they appear to have novel pharmacological sensitivities. Specifically, our results are consistent with the schistosome TRPA channel (SmTRPA) having at least some of the pharmacological sensitivities of mammalian TRPV1 channels, particularly notable as there are no TRPV channels represented in schistosome genomes. Preliminary functional expression studies support this contention. We hypothesize that in schistosomes, SmTRPA fulfills some of the roles of missing TRPV channels. We also hypothesize that SmTRPA and perhaps other schistosome TRP channels regulate critical parasite-host interactions required for successful infection. This project will use parallel strategies to define the roles SmTRPA and other TRP channels play in schistosome biology, including parasite-host interactions, and assess SmTRPA channel function directly. Finally, we hypothesize that the schistosome TRP channel, SmTRPML, plays key roles in schistosome endolysosomal physiology that can impact autophagy and nutrient acquisition. Our studies will elucidate the biological roles and physiological properties of an almost entirely unexplored family of parasite ion channels, information which could in the future be used to provide novel candidate targets for new or repurposed antischistosomal agents. The specific aims of this project are to: 1) Determine the role that SmTRPA and other TRP channels play in the schistosome life cycle, including in parasite-host interactions; 2) Use functional expression to test whether schistosome sensitivity to TRPV1 modulators is mediated specifically by SmTRPA; and 3) Elucidate the role of the schistosome TRPML channel in endolysosomal functions, including nutrient acquisition and autophagy.