Microfluidic devices for high-throughput anthelmintic screens

用于高通量驱虫筛选的微流体装置

• 批准号: 7937008
• 负责人: SHAWN R LOCKERY
• 金额: $ 26.47万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937008
• 关键词: Accounting; Address; Affect; Anthelmintics; Area; Automobile Driving; Body Surface; Caenorhabditis elegans; Chronic; Country; Data Quality; Devices; Disease; Doctor of Philosophy; Drug Industry; Drug resistance; Electrocardiogram; Electrodes; Electrophysiology (science); Engineering; Goals; Heart; Helminths; Home environment; Human; Industry; Infection; Knock-out; Laboratories; Livestock; Malaria; Marketing; Metals; Methods; Microfabrication; Microfluidic Microchips; Microfluidics; Microscopic; Monitor; Muscle; Nematoda; Nematode infections; Nervous system structure; Neuromuscular Junction; Neurons; Parasitic nematode; Pharmaceutical Preparations; Pharmacologic Substance; Pharyngeal structure; Physiological; Population; Prevalence; Principal Investigator; Procedures; Process; Pump; Recruitment Activity; Research; Research Personnel; Resources; Running; Sampling; Screening procedure; Signal Transduction; System; Techniques; Testing; Time; Translational Research; Tropical Disease; base; combat; cost; drug development; drug discovery; feeding; high throughput screening; miniaturize; neglect; neuromuscular; neurophysiology; novel; programs; prototype; public health relevance; public-private partnership; research and development; resistant strain; small molecule libraries

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Research and specific Challenge Topic, 15-AI-103: Develop drugs for neglected tropical diseases, with a special emphasis on malaria. Neglected tropical diseases are a group of 13 major disabling conditions that are among the most common chronic infections in the world's poorest people. Chief among these are the five main diseases caused by nematode worms, accounting for more than 80% of the global prevalence of neglected tropical diseases. Nematode diseases afflict more than a 1/6 of the world's population, yet the anti-nematode drugs - "anthelmintics" - in use today date from the 1960's and 1970's. There is an urgent need for new medications, as research into new anthelmintics has not kept pace with emergence of drug-resistant strains. This problem arises because the resource-limited countries where neglected tropical diseases prevail do not support markets that can offset the enormous cost of drug development. Reducing the cost of drug discovery could do much to increase the flow of better drugs to the people who need them most. The proposed research and development project addresses a critical bottleneck in almost all anthelmintic discovery programs. Developing a new drug starts with a costly screening process that tests hundreds of thousands of compounds. Despite the fact that the majority of anthelmintics act by knocking out essential functions in nervous system, there is as yet no way to screen for compounds that specifically affect the nervous system. The goal of the project is to develop such a screening procedure. The new procedure is based on the observation that the nematode throat, or pharynx, is extremely sensitive to the anthelmintics that also affect the nervous system. The pharynx is a neuromuscular pump involved in feeding. Like the heart, pharynx beats regularly, emitting electrical signals that can monitored on the surface of the body, as in an electrocardiogram or "EKG". In the past year, we have successfully demonstrated a miniaturized recording system that allows researchers to monitor the electrical activity of the pharynx while applying minute quantities of drugs to microscopic nematodes. In the two-year tenure of the proposed research, we will (1) use microfabrication techniques to transform the prototype into a high- throughput screening system and (2) test its ability to identify new anthelmintic agents in partnership with a U.S. pharmaceutical company that is energetically seeking to address the urgent need for new anthelmintics. PUBLIC HEALTH RELEVANCE: Parasitic worms such as nematodes are a major cause of disease in humans and economically important livestock, both at home and abroad. There is an urgent and continuing need for new treatments to combat the rise of drug-resistant nematode strains. This goal of project is to reduce the cost of finding new anti- nematode drugs by developing a new screening process that combines microtechnology and electrophysiology for the first time.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化研究和特定挑战主题，2013年1月15日：开发用于被忽视的热带疾病的药物，并特别强调了疟疾。被忽视的热带疾病是一组由13个主要残疾疾病组成的，是世界上最贫穷的人中最常见的慢性感染之一。其中的主要是线虫蠕虫引起的五种主要疾病，占全球被忽视的热带疾病的80％以上。线虫疾病遭受了世界人口的1/6的困扰，但今天使用的抗新数字药物是“驱虫药” - 从1960年代和1970年代开始使用。迫切需要新的药物，因为对新的驱虫药的研究并没有跟上抗药性菌株的出现。之所以出现这个问题，是因为被忽视的热带疾病的资源有限国家不支持可以抵消药物开发成本的巨大成本的市场。降低药物发现的成本可能会大大增加最需要毒品的人的流动。拟议的研发项目涉及几乎所有驱虫发现计划中的关键瓶颈。开发新药始于昂贵的筛查过程，该过程测试了数十万种化合物。尽管大多数驱虫药通过淘汰神经系统中的基本功能而行动，但尚无筛查特异性影响神经系统的化合物。该项目的目的是制定这样的筛选程序。新程序基于以下观察结果：线虫喉咙或咽，对也影响神经系统的驱虫药极为敏感。咽是参与进食的神经肌肉泵。像心脏一样，咽会定期击败，发出可以在人体表面进行监测的电信号，例如心电图或“ EKG”。在过去的一年中，我们成功展示了一个微型记录系统，该系统使研究人员可以监测咽部的电活动，同时将大量药物应用于微观线虫。在拟议的研究的两年任期中，我们将使用微生物技术将原型转换为高吞吐量筛选系统，以及（2）测试其与美国制药公司合作识别新的驱虫药物的能力，该公司与一家美国制药公司合作，该公司有能量寻求迫切需要新的Anthelelmintics。 公共卫生相关性：在国内外，寄生蠕虫（例如线虫）是人类疾病和经济重要的牲畜的主要原因。紧迫而持续的新疗法需要抵抗耐药线虫菌株的崛起。项目的这个目标是通过开发新的筛查过程，首次结合微技术和电生理学来降低寻找新的抗线虫药物的成本。