Every cell in the human body relies on a constant flow of tiny membrane-bound bubbles—vesicles—to shuttle proteins and fats between its internal compartments and the surface. This project aims to understand the molecular machinery that controls this vesicular traffic, specifically how proteins are delivered to the right place at the right time and how cells break down worn-out components by sending them to the lysosome. This is fundamental cell biology. The problem is that while we know vesicles move cargo, the precise molecular choreography that ensures a protein ends up at the cell surface rather than in the recycling bin remains poorly understood. Without this knowledge, we cannot explain why traffic jams occur in disease. If successful, this work will provide a mechanistic blueprint of membrane trafficking. That blueprint has no immediate practical application—it is curiosity-driven research. However, similar fundamental studies of vesicle transport have already revealed how cholesterol is exported from cells (relevant to atherosclerosis) and how insulin triggers glucose uptake (relevant to diabetes). In the longer term, understanding these pathways could help explain why cells in neurodegenerative diseases fail to clear toxic proteins, and could guide the design of drugs that hitch a ride on specific vesicles to reach precise intracellular targets.
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Humans and animals are made up of millions of cells. Each of these cells is surrounded by a membrane called the plasma membrane made of phospholipids (a type of fat), cholesterol and proteins. The ways in which each cell communicates with other cells, senses its environment and receives nutrition are dependent on the functions of the plasma membrane. The proteins and phospholipids of the plasma membrane are made and degraded inside the cell in specialised organelles (little organs found within each cell) themselves surrounded by membranes also made of phospholipids, cholesterol and proteins. A particularly important organelle involved in the final stages of making the proteins of the plasma membrane is the Golgi complex. An important organelle in their degradation is the lysosome. Interaction between all of these membranes is essential to the correct function of an individual cell. Interaction occurs by membrane traffic, with little vesicles, again each surrounded by a membrane, budding from a donor organelle (or the plasma membrane) and travelling to an acceptor organelle. We aim to understand the molecular mechanisms of this vesicular trafficking. We are concentrating on understanding how the machinery of the membrane traffic system results in individual proteins being delivered to particular intracellular sites and how traffic to and from the lysosome occurs. In the long term our work will contribute to the understanding of many diseases, including diseases such as diabetes, atherosclerosis and neurodegenerative diseases, where defects in the cell surface and/or in membrane traffic occur and infectious diseases where microbes subvert the membrane traffic system in order to infect cells. It will also contribute to developing better ways of targeting drugs to particular sites within cells so that drug therapies may be more specific than at present.
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