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.
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.
| Lockery, Shawn R; Hulme, S Elizabeth; Roberts, William M et al. (2012) A microfluidic device for whole-animal drug screening using electrophysiological measures in the nematode C. elegans. Lab Chip 12:2211-20 |
| Singh, Komudi; Chao, Michael Y; Somers, Gerard A et al. (2011) C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence. Curr Biol 21:825-34 |
