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力。虽然它们对全球农业生产力和动物健康造成严重负担，但它们对人类健康的影响在发展中国家最为深远，因为那里的人口最贫穷，最没有能力科普蠕虫引起的疾病（蠕虫病）。血吸虫属的扁形动物（扁形虫）因其对人类健康的负面影响而臭名昭著，在全球范围内影响了2亿多人。值得注意的是，血吸虫病对人类健康的影响每年造成约7 000万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，已证明抗溶酶体对基于疫苗的控制策略具有抗性，使得非常小的药物组合承担控制负担，几乎完全依赖于抗溶酶体吡喹酮。现在普遍认为，耐药性是过度依赖化疗的必然结果。因此，血吸虫病控制工作继续依赖吡喹酮是一种不可持续的情况，需要政府和慈善机构关注，以解决较贫穷国家的热带疾病负担。血吸虫病的长期有效控制依赖于新型化疗药物的发现和开发。 G蛋白偶联受体（GPCR）是真核生物中最大的蛋白质组之一，是一组特别有利可图的药物靶点。它们在真核生物的信号转导和生理学中起重要作用，介导细胞对多种细胞外刺激的反应。我们开发并部署了一种新的方法来识别染色体GPCR，我们发现了一种新的，独特的受体分支。这些受体构成视紫红质家族GPCR中最大的亚家族，但它们的序列是非常独特的。我们已经标记了这些扁形动物视紫红质孤儿家族1（PROF 1）受体，它们是仅存在于扁形动物中的全新GPCR亚家族。我们的中心假设是，PROF 1受体家族，作为一个臭名昭著的可药用GPCR超家族的扁虫特异性子集，代表了一个合理的目标驱虫药物的发现。我们将定义19个预测的染色体PROF 1受体的时间和相对表达谱。我们的中心假设是，许多PROF 1受体将在哺乳动物内表达的阶段，这将是脆弱的化疗干预。此外，我们将使用RNAi功能询问PROF 1转录抑制的体外后果在童虫和成人的染色体。我们的假设是PROF 1受体参与了对正常寄生虫功能至关重要的过程。该项目的完成将为一种重要的人类寄生虫中的新门特异性GPCR家族产生有价值的生命周期特异性表达数据，并确定有意义的表型终点，这些终点来自可药用宿主内阶段的转录破坏。 公共卫生相关性：该项目将发现有关破坏性人类寄生虫曼氏血吸虫中新发现的受体亚家族的新信息。这些研究将检查这些受体可能成为新一代抗肿瘤药物靶点的可能性。

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.