Endothelial Sphingolipid Signaling in Neurovascular Ischemic Injury

神经血管缺血性损伤中的内皮鞘脂信号转导

基本信息

批准号：
10191065
负责人：
TERESA SANCHEZ GARCIA-VAO
金额：
$ 39.83万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10191065
关键词：
1-Phosphatidylinositol 3-Kinase Acute Anti-Inflammatory Agents Binding Sites Biological Assay Blood - brain barrier anatomy Brain Brain Injuries Cerebral Ischemia Cerebrovascular system Cerebrum Data Endothelium Equilibrium Functional disorder Genetic Genetic Transcription Genomic Segment Human Human Development In Vitro Inflammation Inflammatory Injury Ischemia Kidney Knockout Mice Laboratories Lead Lung Messenger RNA Metabolic Middle Cerebral Artery Occlusion Modeling Molecular Mus NF-kappaB-inducing kinase Neuronal Injury Nuclear Organ Outcome Pathway interactions Permeability Pharmaceutical Preparations Pharmacology Phase Plasma Play Property Proteins Reperfusion Injury Research Resources Rho-associated kinase Role Sepsis Signal Pathway Signal Transduction Solubility Specificity Sphingolipids Stroke Structure Techniques Testing Therapeutic Therapeutic Intervention Transcript Transcription Factor AP-1 Translations Up-Regulation Vascular Permeabilities blood-brain barrier disruption brain endothelial cell cerebral microvasculature cerebrovascular disability improved in vivo in vivo evaluation ischemic injury mRNA Precursor mortality neuroinflammation neurovascular neurovascular injury novel novel therapeutic intervention prevent promoter receptor response rho sphingosine 1-phosphate stroke model stroke outcome systemic inflammatory response targeted treatment translational impact

1-Phosphatidylinositol 3-Kinase Acute Anti-Inflammatory Agents Binding Sites Biological Assay Blood - brain barrier anatomy Brain Brain Injuries Cerebral Ischemia Cerebrovascular system Cerebrum Data Endothelium Equilibrium Functional disorder Genetic Genetic Transcription Genomic Segment Human Human Development In Vitro Inflammation Inflammatory Injury Ischemia Kidney Knockout Mice Laboratories Lead Lung Messenger RNA Metabolic Middle Cerebral Artery Occlusion Modeling Molecular Mus NF-kappaB-inducing kinase Neuronal Injury Nuclear Organ Outcome Pathway interactions Permeability Pharmaceutical Preparations Pharmacology Phase Plasma Play Property Proteins Reperfusion Injury Research Resources Rho-associated kinase Role Sepsis Signal Pathway Signal Transduction Solubility Specificity Sphingolipids Stroke Structure Techniques Testing Therapeutic Therapeutic Intervention Transcript Transcription Factor AP-1 Translations Up-Regulation Vascular Permeabilities blood-brain barrier disruption brain endothelial cell cerebral microvasculature cerebrovascular disability improved in vivo in vivo evaluation ischemic injury mRNA Precursor mortality neuroinflammation neurovascular neurovascular injury novel novel therapeutic intervention prevent promoter receptor response rho sphingosine 1-phosphate stroke model stroke outcome systemic inflammatory response targeted treatment translational impact

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项目摘要

PROJECT SUMMARY Novel therapeutic approaches to minimize neurovascular injury in stroke are needed. The cerebrovascular endothelium not only plays a critical role in blood brain barrier (BBB) disruption and exacerbation of neuronal injury but it also has a great therapeutic potential. However, the limited understanding of the endothelial specific molecular mechanisms involved in BBB disruption restricts progress towards developing novel therapeutic approaches specifically targeting the endothelium in stroke. Sphingosine-1-phosphate (S1P) is highly abundant in plasma, and is a potent modulator of endothelial function via its receptors (S1PR). We and others have shown that S1P via S1PR1 promotes endothelial barrier function in a Gi- phosphatidylinositol-3- kinase-(PI3K)-Akt dependent way in various organs. In sharp contrast, we found that S1PR2 expression is low under basal conditions but its upregulation upon injury induces endothelial permeability as well as endothelial inflammation via activation of G12/13-Rho-Rho kinase (ROCK)-Nuclear Factor-B (NFB) pathway. Therefore, upregulation of S1PR2 switches endothelial S1P signaling from anti-inflammatory to pro-inflammatory. In sepsis models, we have shown that endothelial S1PR2 plays a critical role in the induction of vascular permeability in various organs (e.g. lung, kidney) leading to perpetuation of systemic inflammation. However, in the cerebrovascular endothelium, the specific role of endothelial S1P signaling in BBB disruption upon ischemia and the impact on stroke outcomes are not understood. We found that S1PR2 is transcriptionally upregulated in cerebral microvessels in vivo after ischemia. In addition, global genetic or pharmacological inhibition of S1PR2 prevents the early breakdown of the BBB resulting in decreased neuronal injury. Our in vitro studies have revealed that S1PR2 regulates brain endothelial responses to ischemic injury (e.g. permeability), but not neuronal or glial responses. These findings have provided the basis for our central hypothesis that ischemia-induced transcriptional upregulation of S1PR2 in the endothelium exacerbates BBB dysfunction and brain injury and it can be targeted as novel vasoprotective therapy in stroke. Aim 1 will investigate the role of endothelial S1PR2 signaling in BBB dysfunction and its impact on brain injury, post- ischemic neuroinflammation and stroke outcome. Aim 2 will elucidate the molecular mechanisms governing the expression of S1PR2 in cerebral microvessels upon ischemia. Aim 3 will evaluate the therapeutic potential of targeting this pathway in stroke. Results of the proposed studies will define the novel role of endothelial S1P signaling in BBB dysfunction in stroke and its impact on brain injury. They will also help clarify the molecular mechanisms governing S1P signaling in the cerebrovascular endothelium upon ischemia. Overall, they are expected to have a positive translational impact for novel therapeutic interventions specifically targeting the endothelium in stroke.

项目摘要需要新的热方法来最大程度地减少中风中的神经血管损伤。脑血管内皮不仅在血液脑屏障（BBB）破坏和神经元加剧中起关键作用受伤，但它也具有巨大的治疗潜力。但是，对内皮的有限理解 BBB中断涉及的特定分子机制限制了发展新颖的进展治疗方法专门针对中风内皮。鞘氨醇1-磷酸（S1P）为血浆中高度丰富，是通过其受体（S1PR）的内皮功能的潜在调节剂。我们和其他人则表明，S1P通过S1PR1促进了g-磷脂酰肌醇3-的内皮屏障功能激酶 - （PI3K）-akt依赖于各种器官。相反，我们发现S1PR2表达很低在基本条件下，但在受伤时上调会引起内皮渗透性和内皮通过激活G12/13-RHO-RHO激酶（岩石） - 核因子-IDB（NFB）途径的炎症。所以， S1PR2开关的上调从抗炎到促炎的内皮S1P信号传导。在败血症模型，我们已经表明内皮S1PR2在诱导血管中起着至关重要的作用各种器官（例如肺，肾脏）的渗透性导致全身炎症的持续性。但是，在脑血管上的原始植物，Hothotherium S1P信号在BBB中的特定作用缺血和对中风结果的影响不了解。我们发现S1PR2是转录的缺血后体内脑微血管上的上调。另外，全球遗传学或药理 S1PR2的抑制可防止BBB的早期破裂，导致神经元损伤减少。我们进来体外研究表明，S1PR2调节脑内皮对缺血性损伤的反应（例如渗透性），但没有神经元或神经胶质反应。这些发现为我们的中心提供了基础缺血诱导的S1PR2的转录上调的假设在内皮恶化BBB中功能障碍和脑损伤，并且可以作为中风的新型血管保护疗法的靶向。目标1意志研究内皮S1PR2信号传导在BBB功能障碍中的作用及其对脑损伤的影响，缺血性神经炎症和中风结果。 AIM 2将阐明管理的分子机制 S1PR2在缺血上的脑微血管中的表达。 AIM 3将评估以中风为目标。拟议研究的结果将定义内皮S1P的新作用 BBB功能障碍的信号传导及其对脑损伤的影响。他们还将帮助阐明分子缺血上脑血管内皮中S1P信号传导的机制。总的来说，它们是预计将对新型热干预措施产生积极的翻译影响，专门针对中风中的内皮。