MHI Seminar Series presents Joshua D. Wythe, Ph.D., Associate Professor, Departments of Cell Biology & Neuroscience, University of Virginia School of Medicine

Summary of Seminar:  Brain arteriovenous malformations (bAVMs) are composed of abnormal connections between arteries and veins that lack an intervening capillary network. As a result, high-pressure blood from feeding arteries shunts directly into veins. These structural anomalies undergo extensive remodeling, resulting in a tangle of enlarged blood vessels that are prone to rupture. Accordingly, bAVMs are the leading cause of hemorrhagic stroke in children and young adults. Current treatment options for bAVMs, including surgery, embolization, and radiation all pose a significant risk of disability or death, and these options are not available for ~20% of bAVM patients due to excessive risk. Due to these complications, alternative treatment strategies with lower morbidities, such as targeted pharmacological therapies, are required. Most bAVMs occur sporadically without a family history of the disease. Using whole exome sequencing, Dr. Wythe’s Lab identified somatic, activating mutations in the gene KRAS, which encodes a small GTPase involved in receptor tyrosine kinase signaling. These mutant variants are restricted to the endothelium and result in constitutive KRAS activity. Using mouse and zebrafish models of endothelial-specific expression of mutant KRAS, they demonstrated that these patient variants drive bAVM development in vivo. Using these preclinical cell and animal models, they are determining the mechanisms underlying bAVM disease progression to identify potential therapeutic targets for treating these devastating vascular anomalies.

UNC Lineberger Comprehensive Cancer Center, Pagano Conference Room (LCCC 00-002)
450 West Dr.
Chapel Hill, North Carolina 27599
United States
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