Grant: Operating Grant

A stroke is caused by disturbing the brain's blood supply and frequently leads to a degree of damage in that part of the brain. Depending on the region and area affected, a stroke may result in inability to move an arm or leg on one side of the body, or difficulty speaking. Stroke is recognized to run in families and so has an important genetic basis, with subtle DNA changes, resulting in an increased risk of stroke. At the moment, only a small number of genes have been identified, and the goal of our research is to identify some of the remainder. A key challenge in discovering stroke-causing genes is that stroke usually occurs late in life (generally after the age of 60), at which point individuals who suffer a stroke may be the oldest members of their family. The fact that their parents, and possibly some of their brothers and sisters will have passed away, limits standard genetic analysis to identify stroke-causing genes. We are fortunate in having already identified two genes that when altered (mutated) in patients, result in stroke. Part of our research is to build upon these findings and work out the mechanisms by which subtle changes to these genes alter the brain's blood vessels. This includes further studies in our patients to identify genes that work in the same pathway as those we have identified, and use of an animal model. The ability to turn off the gene of interest in an animal model, and investigate the effect it has on brain blood vessels, is a powerful tool for deciphering the mechanisms involved. We are also fortunate in that quite a bit is known about these two genes, which control the movement of a very specialized group of stem cells to the developing brain. These cells form part of the wall of the brain's arteries, and so changes may result many years later in stroke. This gives us a clue that other genes involved in the same process may also contribute to stroke, and we will test this idea, as part of our experiments.