Grants We Funded

Abstract
Arteriovenous malformation (AVM) is a sporadic, nonhereditary, vascular malformation that is present at birth and can affect any area of the body. Arteries are abnormally connected to veins through irregular blood vessels, instead of a normal capillary network. In the field of vascular anomalies, AVM is the most problematic type of lesion. They enlarge over time and cause disfigurement, ulceration, pain, bleeding, infection and even heart failure and death. Drugs for AVM do not exist and management consists of surgical intervention and/or blocking the affected blood vessels. Unfortunately, AVM has a high recurrence rate after surgery and lesions are rarely cured. Our laboratory recently found that the cells of the blood vessel in most AVMs have mutations in the gene encoding the MAP2K1 protein. Interestingly, the same MAP2K1 mutations are also often found in multiple types of cancer. The goal of this application is to use the novel gene editing technology (CRISPR/Cas9) to introduce the most common AVM causing MAP2K1 mutation (the so-called K57N mutation) specifically into the genome of the blood vessel cells of the laboratory mouse, thereby creating mice that will develop AVMs. We will then take advantage of the fact that cancer research has yielded multiple FDA approved cancer drugs that target the MAP2K1 protein. We will investigate whether treating our AVM mice with these drugs can prevent or slow AVM growth or even reduce the size of the AVM lesions. Successful completion of the proposed experiments will be of high impact and could profoundly impact patients' lives. Our ultimate aim is to translate the results of these studies to clinical trials testing of drugs for AVM.

Biography
After obtaining my PhD in biology at the University of Antwerp (Belgium), I moved to the US, pursuing postdoctoral research first at he Department of Molecular Genetics of the MD Anderson Cancer Center (Houston) and later at the Department of Biomedical Engineering of the Lerner Research Institute of the Cleveland Clinic (Cleveland). My postdoctoral research focused on understanding the molecular mechanisms that control the formation of the skeleton. I worked on two closely related proteins (SOX5 and SOX6) and showed that in their absence cartilage does not form. After my postdoctoral research, I joined the Orthopaedic Research Laboratories at Boston Children’s Hospital. Here, my research focused on skeletal malformations. I was able to identify that Achondrogenesis type IA, a severe dwarfism that is lethal immediately after birth, is caused by mutations in the gene Trip11, which encodes a protein that plays an important role in the movement of proteins within the cartilage cells. Recently, I have switched my research field to the study of vascular anomalies and joined the Department of Plastic and Oral Surgery at Boston Children’s Hospital and Harvard Medical School. My previous research has given me extensive experience in molecular biology and the generation and characterization of mouse models, knowledge that I will now leverage to establish mouse models for vascular malformations to help establish treatments for these disfiguring conditions.