Uncover the Pathogenesis of Brain Arteriovenous Malformation

项目摘要： 脑动静脉畸形（bAVM）患者存在颅内出血（ICH）风险。总体而言， bAVM占50岁以下成人出血性卒中的25%。未破裂病变的治疗 由于这些患者的自然病史可能比侵袭性疾病更少， 治疗bAVM形成的机制尚未完全了解。没有特定的医学疗法 治疗脑动静脉畸形我们是少数几个拥有脑实质中存在bAVM的小鼠模型的小组之一。 使用这些模型，我们已经确定了对bAVM形成和进展至关重要的关键因素。我们 发现血管生成和内皮细胞基因突变的存在是bAVM的必要条件 阵炎症可促进bAVM进展。我们还发现，bAVM血管中 壁细胞覆盖，这与小鼠bAVM和人类中的血管渗漏和出血相关 散发性bAVM。血小板衍生生长因子B（PDGFB）在突变内皮细胞中表达的降低 (ECs)可能是导致壁细胞覆盖减少的原因。我们发现血管抑制 通过贝伐单抗（抗VEGF抗体）治疗的内皮生长因子（VEGF）信号传导，或 静脉内注射表达可溶性FMS相关酪氨酸的腺相关病毒载体（AAV 含有VEGF受体1胞外结构域的激酶1（sFLT 1）抑制bAVM形成， 进展通过沙利度胺治疗增加周细胞覆盖减少了异常血管的数量 和微出血最有趣的发现是，Alk 1或Eng的纯合突变在一部分的 体细胞EC或骨髓来源的EC单独足以触发新生bAVM表型， 在成年小鼠中存在血管生成刺激。巧合的是，其他人最近进行的研究表明， 散发性bAVM和神经外AVM在少数EC中具有体细胞突变。目前尚不清楚A 少数突变的EC可引起bAVM形成。在这个提议中，我们将测试我们的假设，即突变的EC 通过刺激过度血管生成（目的1），损害 周细胞功能（Aim 2）和炎症诱导（Aim 3）。在目标1中，我们将证明突变的EC 经历克隆扩增并释放血管生成因子以刺激邻近正常EC的增殖。 在目标2中，我们将证明突变EC通过减少PDGFB介导的ANG 1而损害周细胞功能， 周细胞中TGF β 1和PDGFRb的表达。在目标3中，我们将展示突变EC驱动小胶质细胞 通过诱导EC-炎症激活、巨噬细胞和淋巴细胞浸润。总体目标 这个项目的目的是寻找新的治疗靶点。

PROJECT ABSTRACT: Patients with brain arteriovenous malformation (bAVM) are at risk of intracranial hemorrhage (ICH). Overall, bAVM account for 25% of hemorrhagic strokes in adults <50 years of age. The treatment of unruptured lesions has become controversial, because the natural history of these patients may be less morbid than invasive therapies. The mechanism of bAVM formation is not fully understood. There are no specific medical therapies to treat bAVMs. We are among a few groups that have mouse models with bAVM in the brain parenchyma. Using these model, we have identified key factors that are crucial for bAVM formation and progression. We found that the presence of angiogenesis and gene mutation in endothelial cells are essential for bAVM formation. Inflammation may promote bAVM progression. We have also found that bAVM vessels have less mural cell coverage, which is associated with vessel leakage and hemorrhage in mouse bAVMs and in human sporadic bAVMs. Reduction of platelet derived growth factor B (PDGFB) expression in mutant endothelial cells (ECs) might be responsible to the reduction of mural cell coverage. We showed that inhibition of vascular endothelial growth factor (VEGF) signaling through bevacizumab (an anti-VEGF antibody) treatment or intravenous injection of an adeno-associated viral vector (AAV) expressing soluble FMS-related tyrosine kinase 1 (sFLT1) containing the extracellular domain of VEGF receptor 1 inhibits bAVM formation and progression. Increase pericyte coverage by thalidomide treatment reduced the number of abnormal vessels and micro-hemorrhage. The most interesting finding is that homozygous mutation of Alk1 or Eng in a portion of somatic ECs or in bone marrow-derived EC alone is sufficient to trigger de novo bAVM phenotype in the presence of angiogenic stimulation in adult mice. Coincidently, recent studies conducted by others shown that sporadic bAVM and extra-neural AVM harbor somatic mutations in a small number of ECs. It is not clear how a few mutant ECs can cause bAVM formation. In this proposal, we will test our hypothesis that mutant ECs cause bAVM formation and progression through stimulating excessive angiogenesis (Aim 1), impairing pericyte function (Aim 2) and induction of inflammation (Aim 3). In Aim 1, we will show that mutant ECs undergo clonal expansion and release angiogenic factors to stimulate the proliferation of adjacent normal ECs. In Aim 2, we will show that mutant EC impair pericyte function through reduction of PDGFB mediated ANG1, TGFb1 and PDGFRb expression in pericytes. In Aim 3, we will show that mutant EC drives microglia activation, macrophage and lymphocyte infiltration through induction of EC-inflammation. The overarching goal of this project is to identify new therapeutic targets.