Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations

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Summary PI3’-Kinase (PI3K) signaling is critical for proper angiogenesis, the development of new blood vessels. However, aberrant PI3K signaling is associated with a wide range of vascular malformations (VMs), including venous malformations which can arise from somatic activating mutations in PIK3CA. VMs are failures in proper endothelial cell development and differentiation giving rise to dysfunctional blood vessels that leave affected patients with significant morbidity and often disfigurement. Our long-term goal is to better understand the molecular etiology of vascular malformations with the hope of contributing novel approaches to the treatment of these conditions non-surgically. We have developed in vitro and in vivo models of PIK3CA-driven VMs and find that the mTORC1 axis may be a critical component of improper vascular morphogenesis. Our central hypothesis is that the mTORC1 axis is being regulated through a novel mechanism; the induction of the mTORC1 regulating protein RHEB. This proposal seeks to determine the role of RHEB in driving malformations arising from PIK3CA mutations and reveal molecular insights into the mechanisms by which RHEB/mTORC1 axis promotes the development of vascular malformations.