Astrocytic integrins in cerebral vessel formation

星形胶质细胞整合素在脑血管形成中的作用

• 批准号: 8451440
• 负责人: Stephen L Nishimura
• 金额: $ 14.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8451440
• 关键词: Adult; Affect; Alleles; Area; Arteriovenous malformation; Astrocytes; Binding; Biological Assay; Biology; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Vascular Malformation; Cell Communication; Cell Differentiation process; Cell Surface Receptors; Cells; Cerebral hemisphere hemorrhage; Cerebrum; Chemicals; Clinical; Coculture Techniques; Complex; Cues; Data; Development; Endoglin; Endothelial Cells; Environment; Event; Feedback; Funding; Genes; Genetic Transcription; Genetic Variation; Genotype; Goals; Hemorrhagic Disorders; Histone Acetylation; Histones; Human; Inflammation Mediators; Inherited; Injection of therapeutic agent; Integrins; Interleukin-1; Interleukin-10; Investigation; Knockout Mice; Knowledge; Lead; Link; MADH4 gene; Maps; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Morphogenesis; Mus; Neuraxis; Neuroepithelial; Neuroepithelial Cells; Neuroglia; Neurons; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathologic; Pericytes; Phenotype; Play; Predisposition; Pregnancy; Promoter Regions; Rattus; Research Personnel; Role; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Testing; Therapeutic; Tissues; Transcription Coactivator; Transcriptional Regulation; Transgenic Organisms; Variant; Vascular Endothelial Growth Factors; angiogenesis; autocrine; base; brain tissue; cell type; chromatin immunoprecipitation; chromatin remodeling; cohort; cytokine; extracellular; genetic variant; insight; loss of function; migration; nestin protein; novel; overexpression; paracrine; prognostic; programs; promoter; receptor; research study; response; transcription factor; vasculogenesis

The long-term goal of this competitive renewal is to understand the mechanistic basis of the cellular interactions required for vessel formation in the central nervous system (CMS). The CMSvasculature differs from the non-CNS vasculature by the presence of the blood-brain barrier (BBB), the formation of which is largely due to interactions with astrocytes. In the past period of support, we have investigated the role that astrocytes play in orchestrating the events that guide proper cerebral vessel development. In particular, we have identified a mechanism for the astrocytic integrin m/p8 in regulating endothelial differentiation. Thus, we have found that astrocytic av(J8-mediatedactivation of TGF-p inhibits endothelial migration and dramatically alters the expression of major endothelial angiogenic and proteolytic factors. This data fills a previous gap in knowledge of the molecular basis for the reciprocal signaling between astrocytes and endothelial cells. Our data suggests that paracrine TGF-p signaling between astrocytes and endothelial cells is the mechanistic basis for the cerebral hemorrhagic phenotype of integrin p8 subunit knock-out mice. TGF-p is essential to normal CNS vasculogenesis since loss of function of the endothelial receptors for active TGF-p, endoglin and Alk-1, lead to hereditary hemorrhagic telangectasia (HHT) in humans and a similar cerebral hemorrhagic disorder in deficient mice. Because TGF-p is ubiquitously expressed in tissues almost entirely in an inactive (latent) state, the avpS-dependent conversion of latent to active TGF-p by astrocytes could be a major regulatory step in the presentation of active TGF-p to CNS endothelial cells. Our preliminary data demonstrate that astrocytes in brain arteriovenous malformation (BAVM) tissues express less P8than control brain tissues; reduced b8 expression is associated with a b8 genotype associated with AVM susceptibility. Furthermore, we have determined that 08 expression in normal astrocytes is dramatically upregulated by IL-10, and that two SNPs in the IL-10 promoter are associated with BAVMsusceptibility and reduced IL-1 ft expression in a cohort of BA VMpatients. These data suggest several mechanisms whereby J38transcription is reduced in BAVMs. We have recently isolated the human and mouse p8 promoters and have identified an IL-1p responsive region. In addition, we have identifiedseveral tag SNPs mapping near the (38 promoter region that show a strong association (p=0.005) with BAVM susceptibility and correlate with reduced expression of (38expression in perivascular cells in BAVM tissue. Finally, we have determined that conditional deletion ofitgbQ in the brain leads to dysplastic neoangiogenesis in response to local VEGF stimulation. Thus, our novel findings support the hypothesis: Decreased astrocytic P8 expression results in reduced avpS-dependent activation of TGF-p causing pathologic alterations of cerebral vascular integrity and differentiation. This hypothesis will beexplored in three

这种竞争性更新的长期目标是了解机械基础 中枢神经系统（CMS）血管形成所需的细胞相互作用。 CMS脉管系统与非CNS脉管系统的不同之处在于血脑的存在。 血脑屏障（BBB），其形成主要是由于与星形胶质细胞的相互作用。过去 在支持期间，我们研究了星形胶质细胞在协调事件中的作用 引导脑血管正常发育的神经系统特别是，我们已经确定了一种机制， 星形胶质细胞整合素m/p8在调节内皮分化中的作用。因此，我们发现， 星形胶质细胞α v β 8介导的TGF-β活化抑制内皮细胞迁移， 改变主要内皮血管生成因子和蛋白水解因子的表达。此数据填充了 先前在相互信号传导的分子基础知识方面的差距， 星形胶质细胞和内皮细胞。我们的数据表明，TGF-β信号的旁分泌， 星形胶质细胞和内皮细胞是脑出血表型的机制基础 整联蛋白p8亚基敲除小鼠。TGF-β对正常CNS血管发生是必需的， 活性TGF-β、内皮糖蛋白和Alk-1的内皮受体的功能丧失，导致 人类遗传性出血性毛细血管扩张症（HHT）和类似的脑出血性毛细血管扩张症（HHT） 缺陷小鼠的疾病。由于TGF-β在组织中普遍表达，几乎完全是在 非活性（潜伏）状态，星形胶质细胞将潜伏性TGF-β依赖avpS转化为活性TGF-β 可能是将活性TGF-β呈递给CNS内皮细胞的主要调节步骤。 我们的初步资料表明，星形胶质细胞在脑动静脉畸形（BAVM） 与对照脑组织相比，脑组织表达较少的P8; b8表达减少与脑组织中的 b8基因型与AVM易感性相关。此外，我们已经确定，08 在正常星形胶质细胞中的表达被IL-10显著上调， IL-10启动子与BAVM易感性相关，并在一个受试者中降低IL-1 β表达。 BA VM患者队列。这些数据表明，J38转录的几种机制， BAVM减少。我们最近分离了人和小鼠的p8启动子， 鉴定了IL-1 β应答区。此外，我们还确定了几个标签SNPs作图， 在β 8启动子区域附近，显示与BAVM易感性强相关（p=0.005 并且与BAVM组织中血管周围细胞中β 8表达的降低相关。 最后，我们已经确定，大脑中itgbQ的条件性缺失导致发育不良， 响应于局部VEGF刺激的新血管生成。因此，我们的新发现支持了 假设：星形胶质细胞P8表达减少导致avpS依赖性 TGF-β的活化引起脑血管完整性的病理改变， 分化这一假设将在三个方面进行探讨