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

• 批准号: 9392836
• 负责人: Aaron J Johnson
• 金额: $ 34.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392836
• 关键词: AIDS Dementia Complex; Acute; Acute Hemorrhagic Leukoencephalitis; Alzheimer' s Disease; Antigens; Area; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Brain; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cerebral Malaria; Chemicals; Confocal Microscopy; Cre-LoxP; Critical Pathways; Data; Disease; Disease model; E protein; Epilepsy; Experimental Models; Flow Cytometry; Glioblastoma; Goals; HIV; Human; Immune; Immunohistochemistry; Immunological Models; Inflammation; Inflammatory; Investigation; KDR gene; Laboratories; Magnetic Resonance Imaging; Mammals; Mediating; Modeling; Monitor; Multiple Sclerosis; Mus; Neurons; Neuropilin-1; Pathology; Peptides; Permeability; Plasmodium berghei; Play; Process; Protein Biochemistry; Research; Resolution; Role; Signal Transduction; Solid; Stroke; Syndrome; 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; animal model development; base; behavioral study; brain endothelial cell; cell type; cytokine; 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; vascular contributions

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.

摘要