CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions

CD8 T 细胞介导的血脑屏障紧密连接破坏

基本信息

批准号：
9293869
负责人：
Aaron J Johnson
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293869
关键词：
AIDS Dementia Complex Acute Acute Hemorrhagic Leukoencephalitis Affect Alzheimer&apos s Disease Antigens Area Biological Models Blood - brain barrier anatomy Blood Vessels Brain C57BL/6 Mouse CD8B1 gene Cells Cerebral Malaria Chemicals Confocal Microscopy Cre-LoxP Data Disease Epilepsy Experimental Models Flow Cytometry Glioblastoma Goals HIV Hematopoietic Human Immune Immunohistochemistry Inflammation Inflammatory Investigation KDR gene Laboratories Magnetic Resonance Imaging Mammals Mediating Modeling Monitor Morbidity - disease rate Multiple Sclerosis Mus Neurologic Neurons Neuropilin-1 Pathology Peptides Permeability Plasmodium berghei Play Process Protein Biochemistry Research Resolution Role Signal Transduction Solid Stroke Syndrome T-Lymphocyte TMEV Testing Therapeutic Therapeutic Intervention Tight Junctions Transgenic Mice Traumatic Brain Injury Up-Regulation Variant Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Viral Antigens Viral Hemorrhagic Fevers Work abstracting animal model development base behavioral study brain endothelial cell cell type in vivo in vivo imaging innovation insight intravital imaging intravital microscopy mouse model nervous system disorder neuroinflammation neurovascular unit novel perforin programs receptor two-photon

AIDS Dementia Complex Acute Acute Hemorrhagic Leukoencephalitis Affect Alzheimer&apos s Disease Antigens Area Biological Models Blood - brain barrier anatomy Blood Vessels Brain C57BL/6 Mouse CD8B1 gene Cells Cerebral Malaria Chemicals Confocal Microscopy Cre-LoxP Data Disease Epilepsy Experimental Models Flow Cytometry Glioblastoma Goals HIV Hematopoietic Human Immune Immunohistochemistry Inflammation Inflammatory Investigation KDR gene Laboratories Magnetic Resonance Imaging Mammals Mediating Modeling Monitor Morbidity - disease rate Multiple Sclerosis Mus Neurologic Neurons Neuropilin-1 Pathology Peptides Permeability Plasmodium berghei Play Process Protein Biochemistry Research Resolution Role Signal Transduction Solid Stroke Syndrome T-Lymphocyte TMEV Testing Therapeutic Therapeutic Intervention Tight Junctions Transgenic Mice Traumatic Brain Injury Up-Regulation Variant Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Viral Antigens Viral Hemorrhagic Fevers Work abstracting animal model development base behavioral study brain endothelial cell cell type in vivo in vivo imaging innovation insight intravital imaging intravital microscopy mouse model nervous system disorder neuroinflammation neurovascular unit novel perforin programs receptor two-photon

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项目摘要

Abstract Blood brain barrier (BBB) disruption is an integral feature of neurological diseases as diverse as multiple sclerosis, acute hemorrhagic leukoencephalitis (AHLE), traumatic brain injury, stroke, cerebral malaria, viral hemorrhagic fevers, epilepsy, glioblastoma, alzheimer’s disease, and HIV dementia. A fundamental question in these diseases is the extent inflammatory immune cells contribute to CNS vascular permeability. This lack of understanding currently undermines therapeutic approaches to treat neurological disease in which uncontrolled BBB disruption contributes to pathology. My research program was the first to demonstrate that CD8 T cells have the capacity to disrupt BBB tight junctions using a novel murine model. Using this model, we have developed a tractable approach to dissect immune-mediated mechanisms of vascular endothelial growth factor (VEGF) mediated BBB disruption using a variation of Theiler’s Murine Encephalomyelitis Virus (TMEV) and the Plasmodium berghei ANKA (PbA) model systems. Our central hypothesis is CD8 T cells promote neuronal expression of VEGF which results in disruption of cerebral endothelial cell tight junctions and vascular permeability. We will test our central hypothesis through the following aims: Specific Aim #1 – Determine the extent direct engagement of antigen specific CD8 T cells with neurons promotes VEGF expression and ensuing vascular changes. Specific Aim #2 – Determine the extent neuronal expression of VEGF and its receptors contribute to CD8 T cell-initiated BBB disruption. Specific Aim #3 – Evaluate the contribution of neuronal VEGF to CD8 T cell-mediated BBB disruption in the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria. To our knowledge, no other laboratories have a similar mouse as PIFS that capitalizes on readily inducible acute CNS vascular permeability mediated by a well-defined immune cell type. Confirming the existence of homologous inflammatory mechanisms in humans would be the first step toward therapeutic intervention of neurological diseases in which neuroinflammation induced CNS vascular permeability plays a significant part. To accomplish these aims, we will employ: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy and immunohistochemistry, (d) 2-photon intravital microscopy (e) protein biochemistry, and (f) small mammal MRI.

抽象的血脑屏障（BBB）破坏是神经疾病等多样性的组成部分多发性硬化症，急性出血性白细胞脑炎（AHLE），创伤性脑损伤，中风，脑疟疾，病毒出血发烧，癫痫，胶质母细胞瘤，阿尔茨海默氏病和HIV 失智。这些疾病中的一个基本问题是炎症免疫细胞的程度有助于CNS血管通透性。目前缺乏理解力治疗神经疾病的治疗方法，其中不受控制的BBB破坏有助于病理学。我的研究计划是第一个证明CD8 T细胞的计划具有使用新型鼠模型破坏BBB紧密连接的能力。使用此模型，我们已经开发了一种可剖析的方法来剖析血管的免疫介导的机制内皮生长因子（VEGF）使用Theiler鼠的变体介导的BBB破坏脑脊髓炎病毒（TMEV）和Berghei疟原虫ANKA（PBA）模型系统。我们的中心假设是CD8 T细胞促进VEGF的神经元表达导致脑内皮细胞紧密连接和血管渗透性的破坏。我们将通过以下目的测试中心假设：具体目的＃1 - 确定抗原特异性CD8 T细胞与与神经元促进VEGF表达并随之而来的血管变化。特定目的＃2 - 确定VEGF及其接收器的神经元表达程度有助于CD8 T细胞引发的BBB破坏。特定目的＃3 - 评估神经元VEGF对CD8 T细胞介导的BBB的贡献实验性脑疟疾的疟原虫ANKA（PBA）模型中的破坏。据我们所知，没有其他实验室的鼠标与PIF相似，PIF大写易于诱导的急性CNS血管通透性由明确定义的免疫细胞类型介导。确认人类同源炎症机制的存在将是第一个迈向神经炎症的神经系统疾病的治疗干预措施诱导的中枢神经系统血管通透性起着重要作用。为了实现这些目标，我们将员工：（a）流式细胞术，（b）行为研究，（c）高分辨率共聚焦显微镜和免疫组织化学，（d）2光子室内显微镜（E）蛋白质化学和（f）小哺乳动物MRI。