Project 462009

The smallest vessels of brain supply just the right amount of blood to feed and remove waste from neurons and regulate blood flow supporting cognitive activity. It is no surprise then that Cerebral Small Vessel Disease (SVD) a group of diseases estimated to cause 25% of all stroke, arises from defects in the small vessels of the brain (arterioles, capillaries and venules). SVD doubles the risk of an ischemic stroke and therefore understanding its pathogenesis is urgent. The primary mechanism of SVD is structural dysfunction of the vessel wall resulting in small obstructions, microbleeds, ischemia and cognitive decline. Microbleeds accelerate blood-brain-barrier breakdown and inflammation, exacerbating damage to vessels. This proposal focuses the differentiation of one of the wall cells called 'pericytes'. We have joined forces with an international team that has identified the greatest genetic risk factors for ischemic stroke in humans, focussing on a gene FOXF2 that regulates how pericyte devleop. Preliminary data shows that some people have genetic changes that lead to lower FOXF2 and dysfunctional pericytes. In this project we determine how FOXF2 controls pericyte differentiation by identifying its mechanism of action. We use a mixture of experiments involving human cells to study the human variant, and zebrafish as an animal model to study intact vessels in vivo. We look at the number and structure of pericytes in the developing brain. We use human stem cells to differentiate pericytes in a dish. For both the fish and human models, we look at how the genes that are expressed in both cells are different when FOXF2 is lost. This will give us insight into a major type of stroke and mechanistically how it develops.