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）：血液菌血吸虫的寄生虫，引起血吸虫病，这是一种影响全世界数亿人的热带疾病。目前针对血吸虫病的首选药物是普拉齐特尔。的确，Praziquantel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，尤其是鉴于有报道称寄生虫对praziquantel的抗性。因此，新治疗剂的NEE是紧急的。当前的大多数驱虫药物靶向离子通道，将这些蛋白质验证为出色的治疗靶标。这个高风险的高付款项目将启动对完全未开发的螺旋体离子通道（瞬态受体电位（TRP）通道）的研究。 TRP渠道家族的成员在激活机制和离子选择性方面的变化极为多样，但具有共同的核心结构。它们对于传递感觉信号，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通道目前正在接受激烈的研究，作为治疗疼痛，癌症和各种其他疾病的治疗靶标。我们假设Schistosoms TRP通道对于实现血块生命周期至关重要，该生命周期取决于宿主发现和迁移到宿主内部偏见位点的外部线索，以及细胞内钙的调节。但是，这些通道在血吸虫和其他寄生虫中的功能是完全未开发的。该项目将使用并行策略来定义您在螺旋体生理中所起的作用，并有可能为新的反毒体剂提供新颖的目标。具体目的是：1。确定正常TRP通道功能对血块生存和生理学的遗传和药理破坏的影响，2。在功能上表达并确定S. mansoni TRP通道子集的特性和药理敏感性。 公共卫生相关性：血吸虫病是一种主要的热带疾病，影响了全球数亿。它是由称为血吸虫的寄生虫引起的。目前，通常只用一种药物来治疗血吸虫病，这是一种非常危险的情况。 显然，需要新的反毒素剂。许多针对寄生虫侵染的药物靶向离子通道，这对于寄生虫神经肌肉的正常功能至关重要。因此，作为新驱虫药物的潜在靶标，离子通道是一个绝佳的选择。该探索性项目将使用多种方法来研究以前没有研究过的螺旋体离子渠道家庭，目的是确定它们在寄生虫生命周期中所起的作用，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。