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

测定新型扁虫特异性 GPCR 家族的驱虫潜力

• 批准号: 8423330
• 负责人: Timothy A Day
• 金额: $ 7.4万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-08 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423330
• 关键词: AIDS/HIV problem; Accounting; Address; Adult; Agriculture; Animals; Anthelmintics; Attention; Biological; Biological Assay; Biological Process; Biology; Cestoda; Data; Dependence; Dependency; Developing Countries; Development; Disease; Drug Targeting; Drug resistance; Family; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Genomics; Government; Grouping; Health; Helminth Genes; Helminths; Human; In Vitro; Intervention; Label; Lead; Life Cycle Stages; Ligands; Malaria; Mediating; Molecular; Molecular Bank; Molecular Profiling; Orphan; Parasite Control; Parasites; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Physiology; Platyhelminths; Play; Population; Praziquantel; Process; Productivity; Proteins; Protocols documentation; RNA Interference; Refractory; Relative (related person); Reporting; Resources; Rhodopsin; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Shoulder; Signal Transduction; Staging; Stimulus; Structure; Transcript; Trematoda; Tropical Disease; Tuberculosis; United States National Institutes of Health; Vaccines; Validation; base; burden of illness; chemotherapy; coping; design; disability-adjusted life years; drug discovery; extracellular; genome sequencing; grasp; improved; novel; novel strategies; pathogen; receptor; receptor function; research study; response; screening; statistics; success

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.

描述（由申请人提供）：蠕虫寄生虫对世界的健康和经济有着强大的控制力。尽管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，因为这些国家的人口最贫困且最无力应对蠕虫引起的疾病（蠕虫病）。血吸虫属扁形虫（扁形虫）因其对人类健康的负面影响而臭名昭著，全世界有超过 2 亿人受其影响。值得注意的是，血吸虫病对人类健康的影响每年造成约 7000 万残疾调整生命年 (DALY) 的损失，超过了疟疾或结核病，与报告的艾滋病毒/艾滋病损失相当。到目前为止，血吸虫已被证明对基于疫苗的控制策略无效，因此只有很少的药物组合承担了控制负担，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，血吸虫病控制工作继续依赖吡喹酮是一种不可持续的情况，需要负责解决较贫穷国家热带疾病负担的政府和慈善机构的关注。血吸虫病的长期有效控制取决于新型化疗药物的发现和开发。 G 蛋白偶联受体 (GPCR) 是最大的真核蛋白类群之一，代表着一组特别有利可图的药物靶标。它们在真核信号转导和生理学中发挥着重要作用，介导细胞对各种细胞外刺激的反应。我们开发并部署了一种新方法来识别血吸虫 GPCR，并且发现了一个新的、独特的受体进化枝。这些受体构成了血吸虫中视紫红质家族 GPCR 的最大亚家族，但它们的序列非常独特。我们已经标记了这些扁形动物视紫红质孤儿家族 1 (PROF1) 受体，它们是仅存在于扁虫中的全新 GPCR 亚家族。我们的中心假设是，PROF1 受体家族作为众所周知的可药物 GPCR 超家族的扁虫特异性子集，代表了驱虫药物发现的合理目标。我们将定义 19 种预测的血吸虫 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表达，从而容易受到化疗干预。此外，我们将使用 RNAi 功能性地探讨血吸虫和成虫血吸虫中 PROF1 转录抑制的体外后果。我们的假设是 PROF1 受体参与对正常寄生虫功能至关重要的过程。该项目的完成将为重要的人类寄生虫中的新型门特异性 GPCR 家族产生有价值的生命周期特异性表达数据，并确定可药物宿主内阶段转录破坏所产生的有意义的表型终点。