Grant: Project Grant

Brain blood vessels support critical cognitive tasks through dynamically adjusting the delivery of oxygen and nutrients needed for brain function. Small vessels (small arteries, arteries, capillaries and venules) are critical for directly feeding tissues. Cerebral small vessel disease (SVD) leads to stroke and vascular dementias and accounts for ~20% of stroke. While age increases risk for SVD, recent evidence suggests it is a lifespan disease, since brain MRI changes consistent with SVD are evident in normal people in their 20's. We and others have shown that several genes implicated in population studies by common variants associated in humans with SVD are 1) developmentally expressed and 2) are associated with development of vascular mural (wall) cells that of small blood vessels. My lab has strong expertise in elucidating developmental pathways for vascular stabilization that intersect with human disease. We have recently identified that nkx3.1 is an early precursor marker critical for generating the right number of pericytes. We also find that it promotes the expression of Versican (VCAN), an extracellular matrix gene identified in large population studies as associated with extreme SVD in humans, and also associated with SVD imaging in young adults. We hypothesise that transcriptional control of pericyte development results in the correct amount and type of ECM deposition necessary for long term brain stabilization.