Molecular Mechanisms Regulating PIK3CA-induced Venous Malformations

摘要 PI3‘-Kinase(PI3K)信号对正常的血管生成、新血的发育至关重要 船只。然而，异常的PI3K信号与广泛的血管 畸形(VM)，包括可由躯体激活引起的静脉畸形 PIK3CA基因突变。VMS是内皮细胞正常发育的失败， 分化导致血管功能障碍，使受影响的患者患上 严重的发病率和通常的毁容。我们的长期目标是更好地了解 血管畸形的分子病因学，希望贡献新的方法来治疗 非手术治疗这些疾病的非手术治疗。我们已经开发了体外和体内模型 发现mTORC1轴可能是不正确的关键组件 血管形态发生。我们的中心假设是mTORC1轴正在被调节 通过一种新的机制：mTORC1调节蛋白Rheb的诱导。这 一项旨在确定Rheb在驱动PIK3CA引起的畸形中的作用的提案 突变和揭示Rheb/mTORC1轴机制的分子见解 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.