Grant: Project Grant

In response to a large class of drugs called Cationic Amphiphilic Drugs (CADs), 100,000s of people experience life-threatening side effects that result in the toxic accumulation of fats in their liver cells through a process called phospholipidosis (PLD). Drugs that are CADs do not induce PLD as part of their intended mechanism of action, but instead do so because the chemical properties of CADs disrupt the function of a major fat-processing system in the cell called the lysosome. When disrupted, excess fats accumulate and will ultimately kill the cell. Through genetic analyses, we have discovered a robust CAD defense system in the small animal model C. elegans, which is a free-living nematode worm. Upon encountering CADs, the animal up-regulates the expression of proteins that will detoxify its cells from the CADs. Without this system, the animal is more vulnerable to CAD-induced pathology. The objective of our project is to understand how animals defend against CAD-induced PLD at a mechanistic level. We will leverage these mechanisms to identify candidate drugs that will suppress the detrimental CAD-induced PLD side effects. To better understand CAD detoxification, we will investigate: i) how CADs up-regulate the expression of CAD-detoxification proteins, and ii) how these proteins modify the CAD molecules to make them less toxic. Our data indicates that we have identified only some of the components that detect the presence of CADs in the cell. To identify other components, we have designed a screen that will reveal additional genes that are required to turn on the CAD defense system. Finally, we will perform screens to identify drugs that may be used to suppress CAD side effects and investigate how they do so. Our work promises foundational insights into how animals defend against CADs and will offer candidate therapies to treat life-threatening CAD-induced liver damage.