Cells are in constant communication with their extracellular environment and neighboring cells: they exchange signals and nutrients that are needed for their life (homeostasis). In our lab, we study the fundamental process whereby cells uptake such molecules, called endocytosis. First, the cellular membrane surrounds these molecules and folds inwards to internalize them. Nutrients and signals enter the cells encapsulated in small, round containers, called vesicles. Once inside the cell, these vesicles travel to different cellular compartments to deliver their cargo to their correct destination. Eventually, these molecules are routed to the digestive center of the cell, called lysosome, where they are degraded.
Endocytosis is not only a mechanism for nutrient uptake, but also a way of cell communication and regulation: decisions such as which signals should reach the interior of the cell and for how long they are active are regulated by this process. In this respect, endocytosis is a mechanism that controls the input of signals and translates it into cell functions: cell growth and death (proliferation and apoptosis), cell identity acquisition (differentiation) and communication between neighboring cells (signaling).
We are interested in understanding how defects in endocytosis lead to human diseases. For this we focus on the liver, the key metabolic organ of our body. We study how liver cells communicate with each other to form a complex tissue and how defects in endocytosis can perturb liver function leading to metabolic disorders and cholestasis.
Pathogens use endocytosis to invade cells and infect the host organism. We are particularly interested in the Mycobacterium, the infectious agent responsible for tuberculosis, a disease that kills around 1.7 million people per year. We want to identify new chemicals that induce the killing of the Mycobacterium by the defense mechanism of the host. For this, we develop computational approaches to monitor the changes of the endocytic system in response to current as well as novel tuberculosis drugs and understand their mechanism of action. This knowledge can not only lead to the design of novel, more effective treatments against tuberculosis, but also other infectious diseases.
Huntington’s disease is a neurodegenerative disorder that impairs muscle coordination and cognitive capacity. We have discovered that endocytosis is perturbed in Huntington’s disease and we are currently using a combination of computational biology with chemical screens to understand the exact mechanism. In collaboration with the CHDI foundation, we are aiming to contribute to the discovery of novel drugs against the disease.
Technology development for therapeutical purposes
Finally, we exploit endocytosis to develop technologies that deliver molecules in a specific tissue and organ. In particular, we use the endocytic system to deliver synthetic small interfering RNAs (siRNAs) in liver, to turn off the expression of genes of interest. This strategy can be used to study gene function in liver but it can also serve as a way of turning off the activity of disease causing genes, thus contributing to the design of clinical treatments. Our ultimate goal in this project is to develop methods of delivering siRNA in a specific tissue and organ that can be used for therapeutic purposes.