Blood-Brain Barrier in Neuroinflammation

神经炎症中的血脑屏障

• 批准号: 8550172
• 负责人: ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
• 金额: $ 36.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550172
• 关键词: Address; Affect; Alzheimer' s Disease; Area; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; CCL2 gene; CXCL1 gene; Central Nervous System Diseases; Characteristics; Chronic; Chronic Phase; Clinical; Complex; DYSF gene; Data; Disease; Disease Progression; Down-Regulation; Drug Delivery Systems; Encephalitis; Endothelial Cells; Epilepsy; Event; Extravasation; Foundations; Functional disorder; Future; HIV encephalitis; IL6 gene; Infection; Inflammation; Inflammatory; Inflammatory Response; Intercellular Junctions; Interleukin-10; Inulin; Ischemic Stroke; Lead; Leukocytes; Meningitis; Methods; Middle Cerebral Artery Occlusion; Molecular; Multiple Sclerosis; Mus; Neuraxis; Parkinson Disease; Pathway interactions; Permeability; Process; Protein Kinase; Proteins; RANTES; Recovery; Regulation; Reperfusion Injury; Research; Role; Route; Signal Transduction Pathway; Signaling Molecule; Sodium Fluorescein; Solid; Stroke; TNF gene; Testing; Tight Junctions; Time; Tracer; Trauma; Traumatic Brain Injury; Vascular Dementia; Vascular Endothelial Cell; Water; angiogenesis; brain remodeling; chemokine; claudin-1 protein; cytokine; improved; microbial; molecular size; neuroinflammation; novel; novel therapeutics; occludin; post stroke; protein expression; protein protein interaction; research study; small molecule; stroke recovery; therapeutic development

DESCRIPTION (provided by applicant): Increased blood-brain barrier (BBB) permeability represents a classic hallmark of central nervous system inflammation that occurs in a variety of neuropathological conditions. In generally the range of increase of BBB permeability goes from intensive remodeling of the brain interendothelial cell junction, (vascular endothelial cell contraction, altered distribution of endothelial intercellular junction proteins) which lead to wid "opening of paracellular route - BBB breakdown to BBB leakage, a selective permeability for small molecular size compounds without "visible" remodeling of TJ complex. BBB leaking is seen in many disease states like Alzheimer and Parkinson disease, vascular dementia, and epilepsy but also in the process of BBB recovery after ischemic episodes or inflammation. Insofar as the accumulating evidences define the morphological alteration and underlying mechanism of the TJ alteration in BBB breakdown, very little is know about type of alteration and mechanism of BBB leaking. In order to elucidate cause and mechanism of persistent BBB leakage develop after postischemic inflammatory response we propose a research plan directed at testing of the following hypothesis: The persistent leakage of BBB after brain ischemic/reperfusion injury is caused by structural alteration of transmembrane TJ proteins that develops in chronic post-stroke inflammatory conditions. The present study will determine; a) the characteristics of TJ complex and BBB functionality after brain I/R injury, b) the type of claudins protein-protein interactions essential for the tightness and stability of TJ complex in brain endothelial cells, c) the signal transduction pathways involved in regulation of prolonged leakage of BBB after brain I/R injury and d) the pathways that improve the brain endothelial barrier after stroke onset. Collectively, these studies will provide new information related to the mechanisms of BBB paracelluar permeability that is relevant to multiple disease states and will, hopefully, elucidate methods for controlling this event.

描述（由申请方提供）：血脑屏障（BBB）通透性增加代表了中枢神经系统炎症的典型标志，发生在各种神经病理学疾病中。通常，BBB渗透性增加的范围从脑内皮细胞间连接的强烈重塑（血管内皮细胞收缩，内皮细胞间连接蛋白的改变的分布）开始，这导致细胞旁途径的广泛“开放- BBB破裂到BBB渗漏，对于小分子尺寸化合物的选择性渗透性，而没有TJ复合物的“可见”重塑。BBB泄漏见于许多疾病状态，如阿尔茨海默病和帕金森病、血管性痴呆和癫痫，但也见于缺血发作或炎症后的BBB恢复过程中。尽管越来越多的证据确定了BBB破裂时TJ改变的形态学改变和潜在机制，但对BBB破裂时TJ改变的类型和机制知之甚少。为了阐明缺血后炎症反应后持续性血脑屏障渗漏的原因和机制，我们提出了一个研究计划，旨在验证以下假设：脑缺血/再灌注损伤后血脑屏障持续性渗漏是由慢性卒中后炎症状态下跨膜TJ蛋白的结构改变引起的。本研究将确定; a）脑I/R损伤后TJ复合物和BB B功能的特征，B）脑内皮细胞中TJ复合物的紧密性和稳定性所必需的密蛋白-蛋白相互作用的类型，c）参与调节脑I/R损伤后BBB的延长渗漏的信号转导途径和d）中风发作后改善脑内皮屏障的途径。总的来说，这些研究将提供有关 BBB细胞旁通透性的机制与多种疾病状态相关，并有望阐明控制该事件的方法。