Determining the pathophysiology of pediatric arteriovenous malformation

本项目的目标是了解动静脉畸形(Avm)的发病机制。 表格和进度。这将使我们了解血管形态发生的基本过程。 而且，重要的是，确定特定的基因/途径，针对这些基因/途径可以开发靶向治疗 改善受AVM和其他血管疾病影响的患者的生活。AVM在出生时就存在 并随着时间的推移经历显著的进展。皮损扩大、出血、溃烂，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，AVM没有治愈方法，也不存在药物治疗。 我们最近发现，大多数人类动静脉畸形都包含MAP2K1的体细胞突变，这 突变是内皮细胞所独有的。我们现在的目标是：(1)确定其他体细胞突变 人类动静脉畸形，(2)决定MAP2K1突变如何影响内皮细胞功能，以及(3)发展 建立动静脉动静脉畸形的动物模型，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进行分子倒置探针、RNA、全外显子组和全基因组测序 组织和分离的内皮细胞，以发现人类动静脉动静脉畸形的额外突变。突变内皮细胞 将对含有MAP2K1突变的细胞进行研究，以确定该突变如何影响信号转导 途径、蛋白质生产和细胞与周细胞相互作用形成血液的能力 船只。通过植入突变的MAP2K1内皮细胞将建立AVM的动物模型 转化为免疫缺陷小鼠，就像我们成功地处理其他类型的血管异常一样。 FDA批准的MAP2K1抑制剂将在体外和体内进行测试，以了解 研究突变如何影响细胞行为的病理生理学，并确定药物的疗效。 这些实验将对我们成功鉴定病理生理产生很大的影响。 负责脑动静脉畸形的形成和扩大。我们将第一次能够追求一个 治疗这种病变的靶向方法。例如，路径特定的局部、区域内和/或 可以开发系统的药理学药物来防止AVM的进展或复发。 对动静脉畸形病理生理学的发现也将有助于我们理解 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 各种各样的疾病。

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.