Roles of Nogo-B receptor in maintaining the structural integrity of blood vessels

Nogo-B 受体在维持血管结构完整性中的作用

• 批准号: 10254256
• 负责人: QING MIAO
• 金额: $ 51.18万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254256
• 关键词: Automobile Driving; Binding; Blood Vessels; Brain; CCM1 gene; Caliber; Cell Surface Receptors; Cell membrane; Cells; Cerebral hemisphere hemorrhage; Cerebrovascular system; Data; Defect; Development; Diagnosis; Elements; Endothelial Cells; Endothelium; Etiology; Exhibits; FDA approved; Family; Functional disorder; Funding; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Transcription; Germ-Line Mutation; Goals; Headache; Health; Histology; Human; Impairment; In Vitro; Intercellular Junctions; Intracranial Hemorrhages; Knockout Mice; Knowledge; Lead; Lesion; Link; Mediating; Membrane; Mission; Molecular; Morphogenesis; Mus; Neurologic; Neurologic Deficit; Nuclear Translocation; Pathogenesis; Pathway interactions; Patients; Pattern; Pericytes; Pharmaceutical Preparations; Phenotype; Play; Promoter Regions; Ras Signaling Pathway; Reporting; Research; Risk; Risk Factors; Role; Seizures; Signal Pathway; Small Interfering RNA; Spinal; Structure; Testing; Tissues; Transcript; Transcriptional Activation; United States National Institutes of Health; Yolk Sac; angiogenesis; base; brain endothelial cell; cell assembly; cerebral cavernous malformations; cerebrovascular; cerebrovascular lesion; disability; human data; human subject; improved; in vivo; insight; loss of function mutation; malformation; novel; novel therapeutic intervention; polarized cell; prevent; receptor; receptor binding; receptor expression; recruit; stroke risk; therapy development; transcription factor

PROJECT ABSTRACT Cerebral cavernous malformations (CCMs), which can occur in 1 out of every 200 people in the US, cause seizure and cerebral hemorrhage. Previous studies have shown that decreased expression or a loss-of-function mutation of CCM family genes (CCM1, CCM2, CCM3) causes CCMs. Although the genetic origins of familial CCMs (20% of cases) have been well characterized, the etiology of sporadic CCMs (80% of cases) that do not carry a germline mutation in CCM genes remains to be established. The long-term goal of our research is to determine if and the extent to which Nogo-B receptor (NgBR) deficiency plays a causal role in the etiology of sporadic CCMs. Support for this idea comes from our previous R01-funded studies where we not only elucidated the molecular mechanisms by which NgBR binds farnesylated Ras to promote angiogenesis but also identified that the NgBR-mediated Ras pathway regulates the expression and activation of transcription factors in endothelial cells. Interestingly, these transcription factors have their binding elements in the promoter regions of CCM1 and CCM2 genes. Consequently, transcript levels of CCM1 and CCM2 genes decrease in NgBR-deficient human brain endothelial cells in vitro and in the yolk sac of NgBR endothelial cell-specific knockout (ecKO) mice in vivo. Additional support of the NgBR-CCM connection comes from histology studies showing that NgBR immunostaining intensity is significantly decreased in endothelial cells (ECs) of human sporadic CCM lesion tissue sections. NgBR ecKO mice have aberrant patterns of cerebral blood vessel assembly, which results in defective EC polarization and the formation of dilated blood vessels. This phenotype is surprisingly similar to the CCM lesions. In addition, the pericyte layer around blood vessels in NgBR ecKO mice is much thinner than littermate control mice. This means that endothelial NgBR deficiency can actually impair pericyte recruitment, which is known as essential for maintaining the structural integrity of blood vessels. Based on these findings, we hypothesize that the NgBR-Ras signaling pathway regulates CCM1/2 expression, and that disrupting this signaling pathway results in cerebrovascular malformation. We will test this hypothesis in three aims. Aim 1: Determine the role of the NgBR-CCM1/2 axis in regulating EC polarization and cerebral blood vessel assembly; Aim 2: Determine the role of the NgBR-CCM1/2 axis in maintaining pericyte recruitment and the structural integrity of cerebral blood vessels; Aim 3: Determine the mechanisms by which NgBR regulates CCM1/2 transcription and the contributions of NgBR-Ras pathway deficiency to the pathogenesis of sporadic CCM. The studies proposed here will establish clear links between NgBR, CCM1/2, and cerebrovascular malformation. Findings from our studies will provide new insight into how NgBR and NgBR-regulated factors guide CCM1/2 expression in brain ECs, and maintain the structural integrity of cerebral blood vessels.

项目摘要 在美国，每200人中就有1人发生脑海绵状血管畸形（CCM）， 癫痫和脑出血以前的研究表明，表达减少或功能丧失 CCM家族基因（CCM 1、CCM 2、CCM 3）的突变导致CCM。虽然家族性的遗传起源 CCM（20%的病例）已得到很好的表征，散发性CCM（80%的病例）的病因学不 携带CCM基因的生殖系突变仍有待确定。我们研究的长期目标是 确定Nogo-B受体（NgBR）缺乏症是否以及在多大程度上在病因学中起着因果作用， 零星的CCM。支持这一想法的是我们之前的R 01资助的研究，我们不仅阐明了 NgBR结合法尼基化Ras促进血管生成的分子机制， NgBR介导的Ras途径调节转录因子的表达和激活， 内皮细胞有趣的是，这些转录因子的结合元件位于转录因子的启动子区。 CCM 1和CCM 2基因。因此，在NgBR缺陷型小鼠中，CCM 1和CCM 2基因的转录水平降低。 体外人脑内皮细胞和NgBR内皮细胞特异性敲除（ecKO）小鼠卵黄囊中的内皮细胞 in vivo. NgBR-CCM连接的其他支持来自组织学研究，表明NgBR 人散发性CCM病变的内皮细胞（EC）免疫染色强度显著降低 组织切片。NgBR ecKO小鼠具有异常的脑血管组装模式，这导致 EC极化缺陷和扩张血管的形成。这一表型与 CCM病变。此外，NgBR ecKO小鼠中血管周围的周细胞层比正常小鼠薄得多。 同窝对照小鼠。这意味着内皮NgBR缺陷实际上会损害周细胞的募集， 已知其对于维持血管的结构完整性是必需的。基于这些发现，我们 假设NgBR-Ras信号通路调节CCM 1/2表达，而破坏这一信号通路， 信号通路导致脑血管畸形。我们将从三个方面来检验这一假设。目标1： 确定NgBR-CCM 1/2轴在调节EC极化和脑血管组装中的作用; 目的2：确定NgBR-CCM 1/2轴在维持周细胞募集和结构调节中的作用。 目的3：确定NgBR调节CCM 1/2的机制 转录和NgBR-Ras途径缺陷对散发性CCM发病机制的贡献。的 本文提出的研究将建立NgBR、CCM 1/2和脑血管畸形之间的明确联系。 我们的研究结果将为NgBR和NgBR调节因子如何指导CCM 1/2提供新的见解 在脑内皮细胞中表达，并维持脑血管结构的完整性。

项目成果

The Role of Histone Protein Acetylation in Regulating Endothelial Function.

• DOI: 10.3389/fcell.2021.672447
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Fang Z;Wang X;Sun X;Hu W;Miao QR
• 通讯作者: Miao QR

NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression.

• DOI: 10.1172/jci151382
• 发表时间: 2022-05-02
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Fang, Zhi;Sun, Xiaoran;Wang, Xiang;Ma, Ji;Palaia, Thomas;Rana, Ujala;Miao, Benjamin;Ragolia, Louis;Hu, Wenquan;Miao, Qing Robert
• 通讯作者: Miao, Qing Robert

NIR-II window tracking of hyperglycemia induced intracerebral hemorrhage in cerebral cavernous malformation deficient mice.

• DOI: 10.1039/d0bm00873g
• 发表时间: 2020-09-21
• 期刊: Biomaterials science
• 影响因子: 6.6