The goal of this project is to understand the mechanism by which arteriovenous malformation (AVM) forms and progresses. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific genes/pathways for which targeted therapies can be developed to improve the lives of patients affected by AVM and other vascular diseases. AVM (not to be confused with hemangioma) is present at birth and undergoes significant progression over time. The lesion enlarges, bleeds, ulcerates, and causes pain and deformity. Vital structures can be threatened and congestive heart failure may occur. Currently, there is no cure for AVM, and drug treatment does not exist. We hypothesize that AVM results from a somatic mosaic mutation because AVM occurs sporadically in the population, is not passed from an affected parent to his/her children, and re-grows following incomplete excision. Therefore, we aim to identify somatic mosaic mutations that cause AVM. We will do this by employing massively parallel sequencing and analysis strategies using the affected and unaffected tissues we have already obtained from patients with AVM. We will also identify the cell type(s) that drive the AVM process. We will do this by purifying endothelial cells, pericytes, progenitor cells, and stromal cells from freshly obtained human AVM tissue. Cells will undergo massively parallel sequencing to determine which cell type(s) are enriched for somatic mutations. Cells also will be used for downstream studies to compare the function of AVM mutant, AVM wild-type, and normal control cells in isolation as well as with co-culture. These experiments will be high impact when we succeed in identifying the somatic mutation responsible for AVM formation and growth. For the first time we would be able to pursue a targeted approach for treating this disease. For example, pathway specific topical, intralesional, and/or systemic pharmacologic agents could be developed to prevent AVM progression or recurrence. Also, discoveries into the cause of AVM will help us understand the mechanisms that underlie other pediatric vascular lesions and improve our ability to identify new pathways for either preventing vascular growth in other disorders (e.g., cancer) or promoting growth during tissue repair or engineering.
Arteriovenous malformations are congenital, pediatric lesions that cause significant suffering in patients, primarily because they grow over time. Children are rarely cured, and drug therapy is not available. This study will determine the reasons for the formation and growth of arteriovenous malformations so that drugs may be developed to keep these lesions small, and prevent their complications.
| Greene, Arin K; Goss, Jeremy A (2018) Vascular Anomalies: From a Clinicohistologic to a Genetic Framework. Plast Reconstr Surg 141:709e-717e |
| Couto, Javier A; Huang, August Y; Konczyk, Dennis J et al. (2017) Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet 100:546-554 |
| Couto, Javier A; Konczyk, Dennis J; Vivero, Matthew P et al. (2017) Somatic PIK3CA mutations are present in multiple tissues of facial infiltrating lipomatosis. Pediatr Res 82:850-854 |
