Grant: Discovery Grants Program - Individual

Each living cell must interact with its surroundings through the molecules present on its outer surface. Proteins are an important type of molecule found on every cell's surface. These cell surface proteins are essential for many cellular functions including the uptake of nutrients such as sugar and vitamins from a cell's surroundings, for attachment to other cells or tissues and for sensing messages from other cells or organisms (e.g. through hormones). The proteins found on a cell's surface work as part of cellular processes that can require a lot of a cell's energy resources, for example in cell movement or migration. Much like household income and expenditures should be balanced, a cell's energetically demanding processes have to be tightly controlled so that energy expenditure is kept in line with a cell's needs and abilities.The long-term goal of our research is to understand how a cell controls the hundreds and perhaps thousands of different types of proteins at its surface to allow that cell to survive and adapt to changing environments. In particular, we seek to understand how a cell senses its own energetic state, and uses this information to control or limit energy-demanding processes that the cell surface. We have recently found that cells have a specific adaptive mechanism to shut down one of their most energy-demanding processes when they sense that they do not have enough energy: cell movement and migration. The key molecular sensor within a cell is a protein called AMP-activated protein kinase (or AMPK), which functions like a cell's fuel gauge; AMPK becomes activated when energy stores are depleted, and works to restore a cell's energy stores. We propose to undertake research aiming to understand how human cells control their surface proteins (in particular those that govern cell migration and attachment) in response to the availability of their own energy stores and fuel production. We will focus on the study of a family of cell surface proteins that control cell migration that are called integrins, and how these are controlled by energy state and AMPK. To do this, we will use advanced forms of microscopy along with tools to “tag” a number of proteins such as integrins with a fluorescent label, which will allow us to “see” them in living cells. Understanding how cell metabolism controls the proteins at the surface of a cell will provide valuable information about a fundamental biological process taking place in virtually every cell in the human body to ensure survival. Through additional experiments, we also plan to reveal how AMPK controls the function of kidney cells, a type of cell that is particularly prone to “energy shortage”. Hence, these experiments will provide new information about kidney function and will provide unprecedented new knowledge about an important, fundamental, yet unexplored phenomenon of biology that controls the behavior of every cell in the human body.