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

基本信息

批准号：
8243599
负责人：
Stephen L Nishimura
金额：
$ 16.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8243599
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

项目摘要

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）中血管形成所需的细胞相互作用。 CMS气流与非CNS脉管系统不同，血脑的存在屏障（BBB），其形成主要是由于与星形胶质细胞的相互作用。在过去支持时期，我们已经调查了星形胶质细胞在策划活动中扮演的角色该指导适当的大脑血管发展。特别是，我们已经确定了一种机制用于调节内皮分化的星形细胞整合素M/P8。因此，我们发现星形胶质细胞AV（TGF-P的J8-介导活化抑制内皮迁移并急剧迁移改变主要内皮血管生成和蛋白水解因子的表达。此数据填充了以前关于在分子基础上的差距的差距星形胶质细胞和内皮细胞。我们的数据表明旁分泌TGF-P信号传导星形胶质细胞和内皮细胞是脑出血表型的机械基础整联蛋白P8亚基敲除小鼠。 TGF-P对于正常CNS血管生成至关重要，因为活性TGF-P，内元和ALK-1的内皮受体功能丧失导致人类中的遗传出血性毛毛虫（HHT）和类似的脑出血缺乏小鼠的障碍。因为TGF-P在组织中普遍表达一种不活跃的状态，即星形胶质细胞对主动TGF-P的AVPS依赖性转换可能是将主动TGF-P向CNS内皮细胞呈现的主要调节步骤。我们的初步数据表明，脑动脉畸形（BAVM）中的星形胶质细胞组织表达较少的P8than对照脑组织；降低的B8表达与A相关 B8与AVM易感性相关的基因型。此外，我们已经确定08 正常星形胶质细胞中的表达大大上调了IL-10，而两个SNP中的两个SNP IL-10启动子与BAVMSutiblesy和A中的IL-1 ft表达降低有关 BA VMPATINTS的队列。这些数据提出了几种机制，J38转录是在Bavms中减少。我们最近分离了人类和小鼠P8启动子，并具有确定了IL-1P响应区域。此外，我们还标识了Several标签SNP映射在（38个启动子区域）附近，该区域显示出与BAVM易感性较强的关联（P = 0.005）并与降低的表达相关（BAVM组织中血管周围细胞中的38例表达。最后，我们确定了大脑中的有条件缺失导致发育不良响应局部VEGF刺激的新血管生成。因此，我们的小说发现支持假设：星形细胞P8表达降低导致AVPS依赖性降低 TGF-P的激活导致脑血管完整性的病理改变和分化。这个假设将在三个