Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations

总结 PI 3 K信号传导对于适当的血管生成、新血液的形成和新生血管的形成至关重要。 船舶.然而，异常的PI 3 K信号转导与广泛的血管病变相关。 畸形（VM），包括可能由躯体激活引起的静脉畸形 PIK 3CA突变。VM是正常内皮细胞发育的失败， 分化引起血管功能障碍，使受影响的患者 严重的发病率和经常的毁容。我们的长期目标是更好地了解 血管畸形的分子病因学，希望有助于新的方法， 这些疾病的非手术治疗。我们已经开发了体外和体内模型 的PIK 3CA驱动的VM，并发现mTORC 1轴可能是一个关键组成部分，不适当的 维管形态发生我们的中心假设是mTORC 1轴受到调节， 通过一种新的机制;诱导mTORC 1调节蛋白RHEB。这 该提案旨在确定RHEB在PIK 3CA引起的驾驶畸形中的作用 突变，并揭示了RHEB/mTORC 1轴 促进血管畸形的发展。

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.