CD 8 T Cell Mediated Disruption of Blood Brain Tight Junction

CD 8 T 细胞介导的血脑紧密连接破坏

基本信息

批准号：
8306282
负责人：
Aaron J Johnson
金额：
$ 33.7万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306282
关键词：
AIDS Dementia Complex Address Adoptive Transfer Affect Animals Area Astrocytes Biological Assay Biological Models Biological Preservation Blood Blood - brain barrier anatomy Blood Vessels Bone Marrow Brain Brothers C57BL/6 Mouse CD4 Positive T Lymphocytes CD8B1 gene Candidate Disease Gene Cells Cellular Immunology Cerebral Malaria Cerebrum Cessation of life Chimera organism Chromosomes Collaborations Data Databases Disease Endothelial Cells Generations Genes Genetic Genetic Variation Goals Health Hematopoietic Hour Human Image Immune Immune system In Vitro Inflammation Inflammation Mediators Inflammatory Informatics Interferons Interleukin-1 Intervention Knowledge Laboratories Lead Link Location Maps Mediating Microsatellite Repeats Modeling Modification Molecular Molecular Biology Monitor Morbidity - disease rate Motor Multiple Sclerosis Mus Neuraxis Neurologic Other Genetics Partner in relationship Pathologic Pennsylvania Peptides Permeability Phenotype Play Predisposition Process Protein Biochemistry Proteins Quantitative Trait Loci Relative (related person)Research Research Personnel Resistance Resources Retroviridae Role Shock Sister Solid Source Stroke Symptoms Syndrome System T cell response T-Lymphocyte TMEV TNF gene Techniques Testing Therapeutic Intervention Tight Junctions Transgenic Mice Universities Vascular Permeabilities Viral Hemorrhagic Fevers Virus Diseases Work base cell type chemotherapy congenic cytotoxic design expectation experience genetic analysis genome wide association study human disease in vivo innovation mortality mouse genome mouse model nervous system disorder novel novel therapeutics perforin reconstitution response retroviral transduction therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Disruption of the Blood Brain Barrier (BBB) is common pathologic feature of numerous serious neurological diseases. Despite the enormous burden of morbidity and mortality due to these neurological diseases associated with CNS vascular permeability, the underlying molecular mechanisms of how inflammatory cells promote BBB disruption remain poorly understood. We have developed a novel murine model of CNS vascular permeability that provides a tractable approach to defining specific inflammatory mediators that disrupt the BBB in vivo using Theiler's virus infection. This murine model of BBB disruption is initiated by peptide-specific stimulation of CNS infiltrating CD8 T cells and is not mediated by TNF-a, IFN-?, LT¿R and IL- 1. However, perforin is critical for both CNS vascular permeability and preservation of BBB tight junctions. Notably, MHC-identical C57BL/6 and 129 Svlm mice differ dramatically in susceptibility to PIFS, despite having identical CD8+ T cell responses and CTL activity. The goal of this proposal is to test our underlying hypothesis that CD8 T cells utilize perforin to initiate the disruption of cerebral endothelial cell BBB tight junctions. Specific modifier genes on the C57BL/6 and 129 SvIm mouse background are also critical for this process to occur. We will determine using this model: 1.) the cellular source of perforin necessary for BBB disruption, 2.) the role of hematopoetic cells in promoting disruption of the BBB, and 3.) the chromosome location of genetic factors that govern BBB disruption. We will use conventional genetic analysis, protein biochemistry, imaging, cellular immunology assays, molecular biology and retrovirus expression to determine the inflammatory factors that mediate disruption of the BBB. Identification of powerful factors that contribute to fatal CNS vascular permeability would define targets for therapeutic modification of the BBB. Such diseases characterized by disruption of the BBB including stroke, viral hemorrhagic fevers, cerebral malaria, HIV dementia, multiple sclerosis (MS), and shock. Increased understanding of BBB permeability could also benefit chemotherapy. PUBLIC HEALTH RELEVANCE: Inflammation mediated blood brain barrier (BBB) disruption is a poorly understood, yet relatively common feature of numerous neurologic diseases. We have developed a novel murine model of CNS vascular permeability that can be utilized to define specific cellular interactions and inflammatory mediators that result in disruption of the BBB in vivo. Defining such factors is the first step towards novel therapeutic modification of BBB permeability.

Description of the Blood Brain Barrier (BBB) is Common Pathologic Feature of Nuurological Despitee The Enormous Burden of Mortality Due to TheSE NEUROLOLOSEASES SSSOCIATED WITH CNS VASCULAR PERMEABITY Lying Molecular Mechanisms of How I Have Development Remain Poor Understood. We Have Developed a novel Murine CNS血管VIDES的模型用于定义特定的炎症者使用其US感染破坏BBB的BBB的模型。 lt¿ R和IL -1。连接。在控制BBB的遗传因素中，HIV痴呆，多发性硬化症（MS）和冲击：炎症介导的血脑屏障（BBB）破坏是一个不足的海洋。导致BBB体内破坏的介体是定义此类因素的第一步。