Grant: Project Grant

Parasitic Helminths (PHs) are major human pathogens. They include the giant roundworm Ascaris lumbricoides as well as whipworms and hookworms. PHs infect over 2 billion people worldwide causing tens of thousands of deaths per year and widespread sickness. PHs are thus a major global health problem and, while there are a few available drugs, resistance is rapidly emerging and there is therefore a great need for new drugs. How can we treat PHs? To do this effectively, we must kill the infecting PH without harming the human host. This means that we need to exploit crucial differences in the biology of humans and PHs. One key possibility lies in the way that humans and PHs make energy. For much of their life cycle, PHs make energy in the same way that humans do. However, when PHs are inside the human body, there is little oxygen available for them - under these conditions, they make energy using an unusual pathway, the FR/RQ pathway, that is completely absent from humans. Drugs that block FR/RQ would thus be ideal anti-PH treatments. No such drugs exist since almost all the simple living systems in which drug screens are done (e.g. yeast, mammalian cells) do not have FR/RQ and so one cannot find FR/RQ inhibitors in these models. The nematode worm C.elegans is different - it has an intact FR/RQ pathway and is easy to grow and study in the lab. We have established conditions in which we can rapidly assay FR/RQ activity in C.elegans. We have also built a novel drug screening pipeline which allows us to screen thousands of drugs per day to find drugs that block FR/RQ. We are therefore in a unique position to attack this major health problem. Our goals are: (1) find which genes are required for FR/RQ and understand how the FR/RQ pathway is regulated. (2) To screen for drugs that inhibit FR/RQ. These are potentially powerful and specific anti-PH drugs. Together, these will be major advances in the treatment of this massive global health challe