Project 458269

Brain arteriovenous malformation (bAVM) is a vascular disease characterized by a tangle of fragile blood vessels formed in the brain of children and young adults. Passage of high-pressure blood through the AVM can result in vessel rupture and stroke. Current treatments include surgical removal; however, this is often dangerous depending on the location of the bAVM. Published work from our lab has identified mutations in the gene Kirsten Rat Sarcoma Virus (KRAS) in patient bAVM samples, specifically in cells lining the vasculature known as endothelial cells (ECs). Expression of mutant KRAS in ECs results in enhanced motility, larger size, and an abnormal cellular appearance. Furthermore, animal models expressing the identified KRAS mutations in ECs, developed bAVM characteristics, such as dilated vessels. Using the bAVM animal and cell culture models that our lab established, I will investigate the role of blood flow in the formation of the bAVM and its maintenance. I will alter fluid flow in a cultured cell system and blood flow will be modulated in zebrafish and I will assess EC structure and function. Furthermore, I will investigate the process of ribosome synthesis and ribosomal RNA processing in ECs as we hypothesize this may be involved in regulating cell size. The findings will collectively indicate the role of altered blood flow and elevated ribosome synthesis and processing in bAVM formation, and may point to novel pharmacological targets to prevent or reverse bAVM formation in a non-surgical manner.