A Novel Strategy to Identify Drugs that Interfere with Endosomal Lipids

Abstract

Lipids are major components of the cell and, like proteins, exhibit much diversity and are highly regulated. And yet, our knowledge of lipids remains limited primarily because their study is difficult. We will use novel Systems Biology approaches, and in particular high content screening techniques, to investigate the mechanisms that regulate the cellular lipid content and function. Our project is to carry out a small compound screen using lipid imaging techniques to identify conditions that interfere with cellular levels and distribution of cholesterol, lysobisphosphatic acid and phosphoinositol-3-phosphate. This forward chemical genetic screen approach should reveal new molecular tools to investigate the molecular mechanism involved in the regulation of these lipids. The aim is to apply chemical proteomic techniques to identify the molecular target(s) of compounds able to affect the intracellular cholesterol regulation and to assess if these are novel druggable targets. This will be the ideal complementary study to the RNAi screen, currently run in our group, as the effect of the inhibition caused by a small molecule can be rapidly reversed when this is removed. Such a small molecule can be administered to a cell or an animal for a very short time to study the function of the target protein and to look at biological mechanisms in a short time-frame. This project is highly interdisciplinary, and will benefit from the help of the screening core facility, currently developed with the support of the NCCR.