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（由申请人提供）：血脑屏障（BBB）通透性增加是多种神经病理学病症中发生的中枢神经系统炎症的典型标志。一般来说，BBB通透性增加的范围来自大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分布改变），这导致“细胞旁途径的开放——BBB破裂到BBB渗漏，在阿尔茨海默病和帕金森病、血管性痴呆等多种疾病中，可以看到小分子化合物的选择性渗透，而没有“可见”的 TJ 复合物重塑。癫痫以及缺血性发作或炎症后的 BBB 恢复过程中，目前越来越多的证据定义了 BBB 破裂中 TJ 改变的形态改变和潜在机制，但对于 BBB 渗漏的改变类型和机制知之甚少。为了阐明缺血后炎症反应后持续 BBB 渗漏的原因和机制，我们提出了一项研究计划，旨在检验以下假设：脑缺血/再灌注后 BBB 持续渗漏损伤是由慢性中风后炎症条件下发生的跨膜 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BBB功能的特征，b)对脑内皮细胞中TJ复合物的紧密性和稳定性至关重要的claudins蛋白-蛋白相互作用的类型，c)参与调节的信号转导途径脑 I/R 损伤后 BBB 长期渗漏的影响，以及 d) 中风发作后改善脑内皮屏障的途径。总的来说，这些研究将提供与 BBB 旁细胞通透性机制与多种疾病状态相关，有望阐明控制该事件的方法。