Venous Malformations (VM): A Murine Mdoel to Identify Therapies to Target Aberrant Venous Development

项目总结/摘要： 静脉畸形（VM）起源于静脉网发育受损，导致大规模的 扩张和功能障碍的静脉。血管病变通常在出生时就存在，随着时间的推移继续扩大， 永远不会自发退化。VM导致显著的发病率和疼痛，通常导致严重的局部和 全身并发症标准的临床治疗包括硬化疗法和手术切除。 然而，由于这些疗法管理症状而不是针对潜在的疾病病因， 畸形静脉经常需要反复干预。因此，VM的新型靶向治疗具有很高的临床应用价值。 重要性 内皮特异性酪氨酸激酶受体TIE 2中的功能获得突变已被鉴定为内皮细胞的功能获得突变。 VM的主要驱动程序。TIE 2已经显示出调节血管静止的维持和促进血管静止。 但是它在血管腔扩张中的作用还没有被探索。研究分子 而由过度活跃的TIE 2引起的细胞异常将为TIE 2的产生提供必要的基础。 VM的靶向分子治疗的发展。我们最近发表的研究结果表明，TIE 2 信号传导促进c-ABL（Abelson激酶1）的活化， 血管腔尺寸显著减小。导致致病性管腔扩张的机制仍然是 在很大程度上尚未探索，c-ABL在VM和血管异常的病理生理学中的作用尚不清楚。 随着TIE 2-c-ABL信号转导轴的新介质的鉴定，我们现在可以开展研究， 该项目旨在研究它们在血管腔扩张中的作用，目的是确定VM的新靶点。 为了进行这些研究，我们将利用我们的VM异种移植小鼠模型和最近设计的体外三- 三维系统来研究VM管腔的形成和扩张。为了加深我们对VM的理解，我们将 采用基于完善的HUVEC-TIE 2-L914 F细胞的互补使用的严格方法 线，VM患者来源的EC和患者组织，以证实我们的发现对于病理生理学的意义。 的VM。 此外，我们对VM的研究将提供细胞和机制的见解，以促进我们对VM的理解。 病理和生理血管形成和尺寸维持。

PROJECT SUMMARY/ ABSTRACT: Venous malformations (VM) originate from impaired development of the venous network, resulting in massively dilated and dysfunctional veins. Vascular lesions are usually present at birth, continuing to expand with time and never spontaneously regress. VM result in significant morbidity and pain often leading to serious local and systemic complications. Standard clinical management consists of sclerotherapy and surgical resection. However, because these therapies manage symptoms rather than targeting underlying disease etiology, malformed veins often require repeated interventions. Therefore, novel targeted therapies for VM are of high importance. Gain-of function mutations in the endothelial-specific tyrosine kinase receptor TIE2 have been identified as the leading driver of VM. TIE2 has been shown to regulate both maintenance of vascular quiescence and promotion of angiogenesis, but its role in the vascular lumen expansion has not been explored. Research into the molecular and cellular abnormalities which result from hyperactive TIE2 will provide the necessary groundwork for the development of the targeted molecular treatments for VM. Our results, recently published, show that TIE2 signaling promotes activation of c-ABL (Abelson kinase 1) and that genetic and pharmacological c-ABL targeting significantly reduced vascular lumen size. The mechanisms leading to the pathogenic lumen expansion are still largely unexplored and the role of c-ABL in the pathophysiology of VM and vascular anomalies is unknown. With the identification of novel mediators of the TIE2-c-ABL signaling axis, we can now develop a research program to investigate their role in vascular lumen expansion with the goal of identifying novel targets for VM. To perform these studies, we will utilize our VM xenograft murine models and a recently devised in vitro three- dimensional system to study VM lumen formation and expansion. To advance our understanding of VM, we will employ a rigorous approach based on the complementary use of the well-established HUVEC-TIE2-L914F cell line, VM patient derived EC and patient tissue to confirm the significance of our findings for the pathophysiology of VM. Additionally, our studies on VM will provide cellular and mechanistic insights to advance our understanding of pathological and physiological vessel formation and size maintenance.