Mechanisms regulating hemangioendothelioma: A plastic surgeon's challenge

项目摘要 血管瘤是婴儿最常见的肿瘤。这些肿瘤会威胁孩子的生命（1%）， 威胁重要结构的发育（10%），并在50%的受影响儿童中造成残余畸形。 大多数发生在头部和颈部区域，导致明显的身体畸形， 为父母苦恼。尽管有这些严重的并发症，大多数受影响的儿童没有得到治疗。 由于目前的药物治疗相关的高风险，安全的缺席 治疗方法的选择是一个关键的障碍，以照顾和良好的临床结果的儿童血管瘤。 在上一轮的资助中，我们发现在2010年1月至2011年12月期间， 增殖性血管瘤的儿童，表明其作为生物标志物的潜在用途。这也是明显的 在我们使用EOMA细胞和经皮递送miR 126的经验证的鼠模型中上调（104 x） 在小鼠模型中，抑制剂导致完全肿瘤消退。miR 126是主要的miR转录物 在发育过程中由内皮细胞表达，转录因子加塔结合蛋白2 GATA 2是胎儿内皮细胞发育的关键驱动因素。两者在EOMA细胞中均上调， 支持血管瘤中的内皮细胞保持持续的胎儿表型的概念范式， 即它们是胎儿休息。该提案将确立miR 126作为血管瘤发展的关键驱动因素 和增殖以及GATA 2作为miR 126生物发生的关键转录调节因子。我们先前已经 报道，标准化的天然浆果提取物（NBE）可以有效地限制血管瘤的发展， 使用EOMA模型的扩散。这种安全的营养干预也抑制了GATA 2/miR 126轴， EOMA细胞。该建议将测试NBE在小鼠模型中抑制血管瘤增殖的能力 以及患有血管瘤的儿童。将评估响应于NBE治疗的miR 126的尿水平的变化。 测量以建立作为生物标志物的效用。本提案的创新之处包括： 从胎儿发育的背景线索，以告知调查线，建立的关键意义， miR调控血管瘤增殖，确定安全的营养干预与 药代动力学数据，以确定第一次在人体给药，并确定和测试生物标志物， 血管瘤成功完成这项提案将改变血管瘤的临床管理， 使所有受影响的儿童都能安全地获得治疗，以防止死亡、残疾或畸形 是由这些肿瘤引起的

Project Summary Hemangiomas are the most common tumors in infants. These tumors can threaten the child's life (1%), threaten the development of vital structures (10%) and cause residual deformity in 50% of affected children. The majority occur in the head and neck area resulting in obvious physical deformity that causes tremendous distress for parents. Despite these significant complications, the majority of affected children do not receive treatment because of the high risks associated with current pharmacologic therapies. The absence of safe therapeutic alternatives is a critical barrier to care and good clinical outcomes for children with hemangiomas. In the previous cycle of funding we discovered markedly elevated levels of microRNA (miR)126 in the urine of children with proliferating hemangiomas indicating its potential usefulness as a biomarker. It is also markedly upregulated (104 x) in our validated murine model using EOMA cells and transdermal delivery of miR 126 inhibitor resulted in complete tumor regression in the murine model. miR126 is the predominant miR transcript expressed by endothelial cells during development and the transcription factor GATA binding protein 2 (GATA2) is critical driver of fetal endothelial cell development. Both are upregulated in EOMA cells, which supports the conceptual paradigm that endothelial cells in hemangiomas retain a persistent fetal phenotype, i.e. they are fetal rests. This proposal will establish miR126 as a critical driver of hemangioma development and proliferation and GATA2 as a key transcriptional regulator of miR126 biogenesis. We have previously reported that a standardized natural berry extract (NBE) can effectively limit hemangioma development and proliferation using the EOMA model. This safe nutritional intervention also inhibits the GATA2/miR126 axis in EOMA cells. This proposal will test the ability of NBE to inhibit hemangioma proliferation in the murine model and in children with hemangiomas. Changes in urinary levels of miR126 in response to NBE therapy will be measured to establish utility as a biomarker. The innovation in this proposal includes: the use of important contextual cues from fetal development to inform lines of investigation, establishing the critical significance of miR regulation of hemangioma proliferation, the identification of a safe nutritional intervention with pharmacokinetic data to determine first in human dosing, and the identification and testing of a biomarker for hemangioma. Successful completion of this proposal will change clinical management of hemangioma by making treatment safely available to all affected children in an effort to prevent death, disability or deformity caused by these tumors.