Determining the pathophysiology of pediatric arteriovenous malformation

本项目的目的是了解动静脉畸形（AVM） 形式和进展。这将使我们了解血管形态发生的基本过程 并且，重要的是，确定可以开发靶向治疗的特定基因/途径， 改善AVM和其他血管疾病患者的生活。AVM在出生时就存在 并且随着时间的推移经历显著的进展。病变扩大，出血，溃疡，并导致 疼痛和畸形。重要结构可能受到威胁，并可能发生充血性心力衰竭。 目前，没有治愈AVM的方法，也不存在药物治疗。 我们最近发现，大多数人AVM在MAP 2K 1中含有体细胞突变， 突变仅限于内皮细胞。我们现在的目标是：（1）确定其他体细胞突变， 人类AVM，（2）确定MAP 2K 1突变如何影响内皮细胞功能，和（3）发展 AVM的动物模型，以进一步研究其病理生理学以及测试药物治疗。我们 将对AVM进行分子倒位探针、RNA、全外显子组和全基因组测序 组织和分离的内皮细胞，以发现人类AVM中的其他突变。突变内皮细胞 将研究含有MAP 2K 1突变的细胞，以确定突变如何影响信号传导 通路、蛋白质产生以及细胞与周细胞相互作用以形成血液的能力 船舶.将通过插入突变的MAP 2K 1内皮细胞来开发AVM的动物模型 移植到免疫缺陷小鼠中，就像我们在其他类型的血管异常中成功地做的那样。 FDA批准的MAP 2K 1抑制剂将在体外和体内进行测试，以了解MAP 2K 1抑制剂的作用。 突变如何影响细胞行为的病理生理学以及确定药物的功效。 这些实验将是高影响，当我们成功地确定病理生理学 负责AVM的形成和扩大。这是我们第一次能够追求 有针对性的方法来治疗这种病变。例如，途径特异性局部、病灶内和/或局部给药。 可以开发全身性药物来预防AVM进展或复发。 对AVM病理生理学的发现也将帮助我们了解AVM的机制， 是其他儿科血管病变的基础，并将提高我们操纵血管生长的能力， 一系列的疾病。

The goal of this project is to understand the mechanisms by which arteriovenous malformation (AVM) forms and progresses. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific genes/pathways for which targeted therapies can be developed to improve the lives of patients affected by AVM and other vascular diseases. AVM is present at birth and undergoes significant progression over time. The lesion enlarges, bleeds, ulcerates, and causes pain and deformity. Vital structures can be threatened and congestive heart failure may occur. Currently, there is no cure for AVM and drug treatment does not exist. We recently found that most human AVMs contain somatic mutations in MAP2K1, and that this mutation is exclusive to the endothelial cell. We now aim to: (1) identify other somatic mutations in human AVMs, (2) determine how MAP2K1 mutations affect endothelial cell function, and (3) develop animal models of AVM to further study its pathophysiology as well as to test pharmacotherapy. We will perform molecular inversion probe, RNA, whole-exome, and whole genome sequencing on AVM tissues and isolated endothelial cells to find additional mutations in human AVMs. Mutant endothelial cells containing the MAP2K1 mutation will be studied to determine how the mutation affects signaling pathways, protein production, and the ability of the cells to interact with pericytes to form blood vessels. An animal model of AVM will be developed by inserting mutant MAP2K1 endothelial cells into immunodeficient mice, as we have successfully done with other types of vascular anomalies. FDA-approved inhibitors of MAP2K1 will be tested in vitro and in vivo to understand the pathophysiology of how the mutation affects cell behavior and to determine the efficacy of the drugs. These experiments will be high impact when we succeed in identifying the pathophysiology responsible for AVM formation and enlargement. For the first time we would be able to pursue a targeted approach for treating this lesion. For example, pathway specific topical, intralesional, and/or systemic pharmacologic agents could be developed to prevent AVM progression or recurrence. Discoveries into the pathophysiology of AVM also will help us to understand the mechanisms that underlie other pediatric vascular lesions, and will improve our ability to manipulate vascular growth in a broad range of diseases.