Mechanisms regulating hemangioendothelioma: A plastic surgeon's challenge

项目摘要 血管瘤是婴儿最常见的肿瘤。这些肿瘤会威胁到孩子的生命(1%)， 威胁生命结构发育(10%)，并在50%的受影响儿童中造成残存畸形。 大多数发生在头部和颈部，导致明显的身体畸形，导致巨大的 对父母来说很痛苦。尽管有这些严重的并发症，但大多数受影响的儿童没有收到 这是因为目前的药物治疗风险很高。保险箱的缺失 治疗替代方案是治疗血管瘤儿童护理和良好临床结果的关键障碍。 在前一个资助周期中，我们发现尿液中的microRNA(MiR)126水平明显升高。 儿童增生性血管瘤提示其作为生物标志物的潜在用途。它也明显地 在我们验证的小鼠模型中，使用EOMA细胞和经皮给药的miR 126上调(104倍) 在小鼠模型中，抑制剂可导致肿瘤完全消退。MiR126是主要的miR转录本 内皮细胞在发育过程中的表达与转录因子GATA结合蛋白2 (GATA2)是胎儿内皮细胞发育的关键驱动因子。两者都在EOMA细胞中上调，这是 支持血管瘤中的内皮细胞保留持续的胎儿表型的概念范式， 也就是说，它们是胎儿的休息。这项提议将使miR126成为血管瘤发展的关键驱动因素 和增殖，GATA2作为miR126生物发生的关键转录调节因子。我们之前已经 报道称，一种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和 使用EOMA模型进行扩散。这种安全的营养干预也抑制了GATA2/miR126轴在 EOMA细胞。这项建议将在小鼠模型中测试NBE抑制血管瘤增殖的能力 对于患有血管瘤的儿童也是如此。NBE治疗后尿miR126水平的变化将是 测量以确定作为生物标记物的实用性。这一建议的创新之处包括：使用重要的 来自胎儿发育的背景线索，以告知调查路线，确立 MIR对血管瘤增殖的调节，确定一种安全的营养干预方法 在人体剂量中首先要确定的药代动力学数据，以及生物标志物的鉴定和测试 血管瘤。这项提案的成功完成将改变血管瘤的临床治疗方式 向所有受影响的儿童提供安全的治疗，努力防止死亡、残疾或残疾 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.