Assaying the Anthelmintic Potential of a Novel Flatworm-Specific GPCR Family

描述(由申请人提供)：蠕虫(蠕虫)寄生虫对世界的健康和经济保持着强大的控制作用。尽管它们是全球农业生产力和动物健康的严重负担，但它们对人类健康的影响在发展中国家最为深远，因为这些国家的人口最贫穷，应对蠕虫引起的疾病(蠕虫硫酶)的能力最差。血吸虫属的扁虫因对人类健康的负面影响位居统计数字之首而臭名昭著，全世界有超过2亿人受到影响。值得注意的是，血吸虫病对人类健康的影响占每年约7000万残疾调整生命年的损失，超过疟疾或结核病，与艾滋病毒/艾滋病报告的损失相当。到目前为止，血吸虫已被证明对基于疫苗的控制策略难以奏效，以至于非常小的药物组合承担着控制的负担，几乎完全依赖于抗血吸虫吡喹酮。现在人们普遍认为，耐药性是过度依赖化疗的必然结果。因此，血吸虫病控制工作对吡喹酮的持续依赖是一种不可持续的情况，需要各国政府和负责解决较贫穷国家热带病负担的慈善机构予以关注。血吸虫病的长期有效控制有赖于新型化疗药物的发现和开发。G蛋白偶联受体(GPCRs)是真核生物中最大的蛋白质组之一，代表着一组特别有利可图的药物靶点。它们在真核细胞信号转导和生理中发挥重要作用，介导细胞对多种细胞外刺激的反应。我们开发和部署了一种新的方法来识别血吸虫GPCRs，我们发现了一种新的、独特的受体分支。这些受体构成了血吸虫视紫红质家族GPCRs中最大的亚家族，但它们的序列是相当独特的。我们已经标记了这些扁形蠕虫视紫红质孤儿家族1(PROF1)受体，它们是全新的GPCR亚家族，仅存在于扁虫中。我们的中心假设是，PROF1受体家族作为扁虫特异性GPCR超家族的一个子集，代表了驱虫药发现的合理靶点。我们将定义19个预测的血吸虫PROF1受体的时间和相对表达谱。我们的中心假设是，许多PROF1受体将在哺乳动物体内的阶段表达，这将容易受到化疗干预的影响。此外，我们将使用RNAi在功能上询问血吸虫幼虫和成虫体内PROF1转录抑制的体外后果。我们的假设是，PROF1受体参与了对寄生虫正常功能至关重要的过程。该项目的完成将为一个重要的人类寄生虫中一个新的门特定的GPCR家族产生有价值的生命周期特异性表达数据，并确定在可用药的宿主内阶段转录中断所导致的有意义的表型终点。 与公共卫生相关：该项目将发现关于毁灭性的人类寄生虫曼氏血吸虫中新发现的受体亚家族的新信息。这些研究将检验这些受体可能成为新一代抗血吸虫药物的靶点。

DESCRIPTION (provided by applicant): Helminth (worm) parasites maintain a powerful grip on the health and economy of the world. Although they are a serious burden on agricultural productivity and animal health globally, their impact on human health is most profound in developing nations where human populations are the poorest and least able to cope with helminth induced diseases (helminthiases). Platyhelminths (flatworms) of the genus Schistosoma are notorious for topping the statistics for negative effects on human health, afflicting over 200 million worldwide. Remarkably, the impact of schistosomiasis on human health accounts for annual losses of approximately 70 million disability-adjusted life years (DALYs), exceeding that of malaria or tuberculosis and being comparable to that reported for HIV/AIDS. So far, schistosomes have proven refractory to vaccine-based control strategies such that a very small portfolio of drugs shoulders the burden of control, relying almost completely on the antischistosomal praziquantel. It is now generally accepted that drug resistance is the inevitable consequence of an over-dependence on chemotherapy. Therefore, the continued dependency of schistosomiasis control efforts on praziquantel is an unsustainable situation and demands attention from governments and charitable bodies tasked with tackling the tropical disease burden in poorer nations. The effective long-term control of schistosomiasis depends upon the discovery and development of novel chemotherapeutics. G protein-coupled receptors (GPCRs) constitute one of the largest groupings of eukaryotic proteins, and represent a particularly lucrative set of pharmaceutical targets. They play an important role in eukaryotic signal transduction and physiology, mediating cellular responses to a diverse range of extracellular stimuli. We developed and deployed a novel approach to identify schistosome GPCRs, and we discovered a new, unique clade of receptors. These receptors constitute the largest subfamily of Rhodopsin family GPCRs in schistosomes, yet their sequences are quite unique. We have labeled these platyhelminth Rhodopsin orphan family 1 (PROF1) receptors, and they are and entirely novel GPCR subfamily that is present only in flatworms. Our central hypothesis is that the PROF1 receptor family, as a flatworm-specific subset of the notoriously druggable GPCR superfamily, represents a rational target for anthelmintic drug discovery. We will define the temporal and relative expression profiles of 19 predicted schistosome PROF1 receptors. Our central hypothesis is that many PROF1 receptors will be expressed in intra-mammalian stages that would be vulnerable to chemotherapeutic intervention. Further, we will use RNAi to functionally interrogate the in vitro consequences of PROF1 transcript suppression in schistosomula and adult schistosomes. Our hypothesis is that PROF1 receptors are involved in processes vital to normal parasite function. The completion of this project will generate valuable life cycle-specific expression data for a novel phylum-specific GPCR family in an important human parasite, and identify meaningful phenotypic endpoints that result from transcript disruption in druggable intra-host stages. PUBLIC HEALTH RELEVANCE: This project will discover new information about a newly-discovered subfamily of receptors in the devastating human parasite Schistosoma mansoni. The studies will examine the possibility that these receptors could be targets for a new generation of antischistosomal drugs.