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)的风险。总的来说， 脑动静脉畸形占50岁以上成人出血性卒中的25%。未破裂性病变的治疗 已经变得有争议，因为这些患者的自然病史可能比侵袭性的病态更少 治疗。BAVM的形成机制尚不完全清楚。没有特定的医学疗法。 治疗脑动静脉畸形。我们是少数几个在脑实质中建立了bAVM小鼠模型的小组之一。 使用这些模型，我们已经确定了对bAVM的形成和进展至关重要的关键因素。我们 发现血管内皮细胞中血管生成和基因突变的存在对bAVM是必不可少的 队形。炎症可能促进bAVM的进展。我们还发现，bAVM血管的 壁细胞覆盖率与小鼠和人类的血管渗漏和出血有关 零星的脑动静脉畸形。突变型内皮细胞中血小板衍生生长因子B表达的降低 (ECS)可能与壁细胞覆盖率降低有关。我们证明了血管的抑制 血管内皮细胞生长因子通过贝伐单抗(一种抗血管内皮细胞生长因子抗体)治疗或 静脉注射表达可溶性FMS相关酪氨酸的腺相关病毒载体 含有血管内皮生长因子受体1胞外区的激酶1(SFlt1)抑制bAVM的形成和 进步。沙利度胺治疗增加周细胞覆盖率减少异常血管数目 和微小出血。最有趣的发现是Alk1或Eng的纯合子突变在一部分 仅在体细胞或骨髓来源的EC中就足以触发新生bAVM表型 成年小鼠血管生成刺激的存在。巧合的是，最近其他人进行的研究表明 散发性bAVM和神经外AVM在少数内皮细胞中存在体细胞突变。目前还不清楚一种 很少有突变的ECs能引起bAVM的形成。在这个提案中，我们将测试我们的假设，突变的ECs 通过刺激过度的血管生成导致bAVM的形成和进展(目标1)，损害 周细胞功能(目标2)和诱导炎症(目标3)。在目标1中，我们将展示突变EC 进行克隆性扩增，释放血管生成因子，刺激邻近正常内皮细胞增殖。 在目标2中，我们将证明突变EC通过减少PDGFB介导的ANG1而损害周细胞功能， TGFb1和PDGFRb在周细胞中的表达。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。首要目标是 这个项目的目的是确定新的治疗靶点。

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.