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: 8496704
• 负责人: ROBERT M GREENBERG
• 金额: $ 22.56万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496704
• 关键词: Adult; Affect; Anthelmintics; Antischistosomal Agents; Behavior; Calcium; Cations; Cell membrane; Cues; Development; Diffusion; Drug Targeting; 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.

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。