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

基本信息

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
项目类别：
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

项目摘要

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 人患有脑海绵状血管瘤 (CCM)，导致癫痫发作和脑出血。先前的研究表明，表达减少或功能丧失 CCM 家族基因（CCM1、CCM2、CCM3）突变会导致 CCM。虽然遗传起源是家族性的 CCM（占病例的 20%）已得到很好的表征，散发性 CCM（占病例的 80%）的病因学尚未明确 CCM 基因是否携带种系突变仍有待确定。我们研究的长期目标是确定 Nogo-B 受体 (NgBR) 缺陷是否以及在多大程度上在病因学中起因果作用零星的 CCM。对这一想法的支持来自我们之前 R01 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，但也已确定 NgBR介导的Ras通路调节转录因子的表达和激活内皮细胞。有趣的是，这些转录因子在启动子区域有其结合元件 CCM1 和 CCM2 基因。因此，NgBR 缺陷的 CCM1 和 CCM2 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) 小鼠卵黄囊中的人脑内皮细胞体内。 NgBR-CCM 连接的额外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) 的免疫染色强度显着降低组织切片。 NgBR ecKO 小鼠脑血管组装模式异常，导致 EC 极化缺陷和血管扩张的形成。这种表型与 CCM 病变。此外，NgBR ecKO 小鼠血管周围的周细胞层比同窝对照小鼠。这意味着内皮 NgBR 缺陷实际上会损害周细胞的募集，众所周知，这对于维持血管结构完整性至关重要。基于这些发现，我们假设 NgBR-Ras 信号通路调节 CCM1/2 表达，并且破坏此信号通路信号通路导致脑血管畸形。我们将从三个目标来检验这个假设。目标 1：确定NgBR-CCM1/2轴在调节EC极化和脑血管组装中的作用；目标 2：确定 NgBR-CCM1/2 轴在维持周细胞募集和结构中的作用脑血管的完整性；目标 3：确定 NgBR 调节 CCM1/2 的机制转录以及 NgBR-Ras 通路缺陷对散发性 CCM 发病机制的贡献。这这里提出的研究将建立 NgBR、CCM1/2 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 CCM1/2 提供新的见解在脑内皮细胞中表达，维持脑血管的结构完整性。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

NOGOB 受体缺陷通过损害组蛋白乙酰化介导的 CCM1/2 表达来增加脑血管通透性和出血。

DOI：
发表时间：
2022-05-02
期刊：
影响因子：
0
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

The Role of Histone Protein Acetylation in Regulating Endothelial Function.

组蛋白乙酰化在调节内皮功能中的作用。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Fang, Zhi;Wang, Xiang;Sun, Xiaoran;Hu, Wenquan;Miao, Qing R
通讯作者：
Miao, Qing R

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

NIR-II 窗口追踪高血糖引起的脑海绵状血管瘤缺陷小鼠脑出血。

DOI：
10.1039/d0bm00873g
发表时间：
2020-09-21
期刊：
Biomaterials science
影响因子：
6.6
作者：
A. Parchur;Zhi Fang;J. Jagtap;Gayatri Sharma;Christopher Hansen;Shayan Shafiee;Wenquan Hu;Q. Miao;Amit Joshi
通讯作者：
Amit Joshi