Microfluidic devices for high-throughput anthelmintic screens

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化研究和具体的挑战主题，15-AI-103：开发被忽视的热带疾病药物，特别强调疟疾。被忽视的热带病是13种主要致残疾病，是世界上最贫穷人口最常见的慢性感染之一。其中最主要的是由蠕虫引起的五种主要疾病，占全球被忽视的热带病流行率的80%以上。线虫病折磨着超过1/6的世界人口，然而今天使用的抗线虫药物-“驱虫剂”-可以追溯到20世纪60年代和70年代。迫切需要新的药物，因为对新驱虫剂的研究没有跟上抗药性菌株的出现。出现这一问题的原因是，被忽视的热带疾病流行的资源有限的国家不支持能够抵消药物开发的巨大成本的市场。降低药物研发的成本可以大大增加更好的药物流向最需要它们的人。拟议的研究和开发项目解决了几乎所有驱虫剂发现计划中的一个关键瓶颈。开发一种新药首先要进行昂贵的筛选过程，测试数十万种化合物。尽管大多数驱虫药通过敲除神经系统中的基本功能来起作用，但目前还没有办法筛选出专门影响神经系统的化合物。该项目的目标是制定这样一个筛选程序。新的程序是基于观察，线虫的喉咙，或咽，是极其敏感的驱虫药，也影响神经系统。咽是一个神经肌肉泵，参与进食。像心脏一样，咽部有规律地跳动，发出可以在身体表面监测的电信号，如心电图或“EKG”。在过去的一年里，我们成功地展示了一个小型化的记录系统，使研究人员能够监测咽部的电活动，同时将微量的药物应用于显微镜下的线虫。在拟议研究的两年任期内，我们将（1）使用微加工技术将原型转化为高通量筛选系统，（2）与一家美国制药公司合作，测试其识别新驱虫剂的能力，该公司正在积极寻求解决对新驱虫剂的迫切需求。 公共卫生相关性：寄生蠕虫如线虫是国内外人类和经济上重要的牲畜疾病的主要原因。迫切需要新的治疗方法来对抗抗药性线虫菌株的增加。该项目的目标是通过首次开发一种结合微技术和电生理学的新筛选过程来降低寻找新的抗线虫药物的成本。

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.