Growth Regulatory Pathways in Vascular Anomalies

描述（由申请人提供）：血管异常是血管发育和生长的先天性失调，包括多种疾病，包括婴儿血管瘤。虽然婴儿血管瘤是常见的，可导致严重的身体和功能障碍的儿童，这种疾病的发病机制知之甚少。已经确定了几种血管瘤的血管生成调节因子。然而，很少有人知道有关的信号机制，调节血管瘤的发展，这些因素。血管瘤细胞具有高水平的激活的Akt，其是血管生长的关键调节因子。有3种已知的Akt亚型，Akt信号传导的不同生物学结果可能部分归因于这些亚型的不同功能。 我们的长期目标是了解生长因子信号通路在调节血管发育和生长中的分子机制。这个建议的目的是解开Akt亚型在血管瘤发展中的生物学作用。我们的具体目标是：（1）研究Akt1和Akt3在血管瘤中的相反功能，以及（2）确定视网膜母细胞瘤结合蛋白4在介导Akt3功能中的作用。这项工作将有助于我们对血管生成中关键信号通路的基本理解，并通过靶向驱动血管瘤生长的关键通路，为患有复杂血管瘤的儿童开辟新的治疗选择。

DESCRIPTION (provided by applicant): Vascular anomalies are congenital dysregulation of vascular development and growth, and consist of a wide spectrum of disorders, including infantile hemangioma. Although infantile hemangioma is common and can cause severe physical and functional impairment for the child, the pathogenesis of this disease is poorly understood. Several angiogenic regulators of hemangioma have been identified. However, little is known regarding the signaling mechanisms that regulate hemangioma development by these factors. Hemangioma cells have high levels of activated Akt, a key regulator of vascular growth. There are 3 known Akt isoforms, and the diverse biological outcomes of Akt signaling may be due in part to the different functions of these isoforms. Our long-term goal is to understand the molecular mechanism of growth factor signaling pathways in the regulation of vascular development and growth. The objective of this proposal is to unravel the biological roles of Akt isoforms in hemangioma development. Our Specific Aims are: (1) to investigate the opposing functions of Akt1 and Akt3 in hemangioma, and (2) to determine the role of retinoblastoma binding protein 4 in mediating the function of Akt3. This work will contribute to our fundamental understanding of key signaling pathways in angiogenesis, and open new therapeutic options for children with complex hemangiomas by targeting critical pathways driving hemangioma growth.