BMP and Notch crosstalk in cerebral arteriovenous malformations

脑动静脉畸形中的 BMP 和 Notch 串扰

• 批准号: 9381141
• 负责人: Yucheng Yao
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381141
• 关键词: Affect; Arteriovenous malformation; Blood Vessels; Bone Morphogenetic Proteins; Brain; Brain hemorrhage; Cell Differentiation process; Cells; Cerebral Arteriovenous Malformations; Cerebrovascular system; Cerebrum; ChIP-seq; Chemicals; Child; Chromatin; DNA Binding; Data; Defect; Development; Diagnosis; Disease; Endothelial Cells; Gene Targeting; Genes; Genetic Transcription; Hereditary hemorrhagic telangiectasia; Human; In Vitro; Lead; Ligands; Lung; Maintenance; Massive Parallel Sequencing; Mediating; Mediator of activation protein; Modeling; Mus; Neurologic; Nucleic Acid Regulatory Sequences; Play; Prevention strategy; Public Health; Recruitment Activity; Regulation; Regulator Genes; Role; Signal Transduction; Signaling Protein; Ski-interacting protein; Technology; Testing; Therapeutic; Tissues; Translating; Vascular Diseases; Vascular Endothelial Growth Factors; Work; Youth; activin receptor-like kinase 1; brain endothelial cell; cerebrovascular; chromatin immunoprecipitation; high throughput screening; in vivo; inhibitor/antagonist; insight; jagged1 protein; knock-down; malformation; matrix Gla protein; notch protein; prevent; receptor; sex; treatment strategy; vascular bed

ABSTRACT Therapeutic advances in vascular disease may have far-reaching public benefits. Bone morphogenetic proteins (BMPs) and Notch signaling are emerging as essential regulators of the vasculature, and important in disorders such as arteriovenous malformations (AVMs). Our previous studies have demonstrated that excess BMP induces Notch signaling causing cerebral AVMs. In preliminary studies, we demonstrate a strong endothelial induction of Sox2 in human cerebral AVMs, and a dramatic improvement of cerebral AVMs after limiting Sox2 in ECs. We find that excess transcriptional activity of Sox2 disrupts cerebral EC differentiation to cause lumen disorder in AVMs. Sox2 is regulated by crosstalk of BMP and Notch signaling. In vitro, we show that BMP-induced Notch ligands Jagged 1 and 2 upregulate Sox2, and knockdown of Notch1 receptor diminishes Sox2 induction. In vivo, Jagged 1 and 2 and Notch1 are increased and directly targeted Sox2 in MGP-deficient cerebral ECs, in which a decrease of Jagged 1 or 2 reduces Sox2 expression. In contrast, we find no induction or significant changes of transcriptional effects of Sox2 in pulmonary AVMs, where instead the expression of VEGF is increased. Limiting endothelial Sox2 does not improve pulmonary AVMs. To induce Sox2, Notch requires ski-interacting protein (Skip), which is active in brain ECs but inactive in pulmonary ECs. Furthermore, we have created a high throughput-screening model and aim to identify chemical compounds that suppress Sox2 expression in brain ECs. We hypothesize that regulation of Sox2 and its transcriptional activity is important in the maintenance of EC differentiation and lumen formation in normal cerebral vasculature. Specific Aim 1 will determine how Sox2 is regulated by BMP and Notch signaling and affects the differentiation of brain endothelial cells. Specific Aim 2 will determine if Sox2 is induced to contribute to human cerebral AVMs. Specific Aim 3 will determine how regulation of Sox2 differs in cerebral versus pulmonary AVMs and identify the chemical compounds that suppress Sox2 expression. If successful, the obtained information may translate into strategies for using Sox2 inhibitors in the treatment of cerebral AVMs. The study may also provide significant insights of tissue-specific formation of AVMs, and lead to different treatment strategies for AVMs.

抽象的 血管疾病的治疗进展可能会产生深远的公共利益。骨形态发生 蛋白 (BMP) 和 Notch 信号传导正在成为脉管系统的重要调节因子，并且在 动静脉畸形（AVM）等疾病。我们之前的研究表明，过量 BMP 诱导 Notch 信号传导导致脑动静脉畸形。在初步研究中，我们展示了强大的 人脑 AVM 中 Sox2 的内皮诱导，以及术后脑 AVM 的显着改善 限制 EC 中的 Sox2。我们发现 Sox2 的过度转录活性会破坏大脑 EC 分化 导致 AVM 管腔紊乱。 Sox2 受 BMP 和 Notch 信号传导的串扰调节。在体外，我们展示 BMP 诱导的 Notch 配体 Jagged 1 和 2 上调 Sox2，并敲低 Notch1 受体 减少 Sox2 诱导。在体内，Jagged 1和2以及Notch1增加并直接靶向Sox2 MGP 缺陷的脑 EC，其中 Jagged 1 或 2 的减少会降低 Sox2 的表达。相比之下，我们 发现肺 AVM 中 Sox2 的转录效应没有诱导或显着变化，相反 VEGF 表达增加。限制内皮 Sox2 不会改善肺 AVM。诱导 Sox2、Notch 需要滑雪相互作用蛋白 (Skip)，该蛋白在脑 EC 中活跃，但在肺 EC 中不活跃。 此外，我们创建了一个高通量筛选模型，旨在识别化合物 抑制大脑 EC 中 Sox2 的表达。我们假设 Sox2 及其转录的调控 活性对于正常大脑中 EC 分化和管腔形成的维持非常重要 脉管系统。具体目标 1 将确定 Sox2 如何受 BMP 和 Notch 信号传导调节并影响 脑内皮细胞的分化。具体目标 2 将确定 Sox2 是否被诱导对人类做出贡献 脑动静脉畸形。具体目标 3 将确定 Sox2 的调节在大脑和肺部有何不同 AVM 并鉴定抑制 Sox2 表达的化合物。如果成功的话，得到的 这些信息可能会转化为使用 Sox2 抑制剂治疗脑动静脉畸形的策略。研究 还可能提供对 AVM 的组织特异性形成的重要见解，并导致不同的治疗 AVM 策略。