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Protective role of let-7 microRNAs in brain endothelial dysfunction during ischemia/reperfusion injury

let-7 microRNA在缺血/再灌注损伤期间脑内皮功能障碍中的保护作用

基本信息

批准号：
10059280
负责人：
Slava ROM
金额：
$ 34.67万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059280
关键词：
Acute Address Adhesions Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Atherosclerosis Attenuated Bioinformatics Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain Ischemia Brain imaging CCL2 gene CXCL10 gene CXCR3 gene Cell Adhesion Molecules Cells Central Nervous System Diseases Cephalic Characteristics Clinical Trials Complementary therapies Development Endothelial Cells Endothelium Epilepsy Event Extravasation FDA approved Family Fibrinolytic Agents Functional disorder Future Gene Expression Genes Glucose Heterogeneous-Nuclear Ribonucleoproteins Human Hypoxia IL8 gene In Vitro Incidence Infarction Infection Infectious Encephalitis Infiltration Inflammation Inflammatory Inflammatory Response Injury Ischemia Ischemic Stroke Knock-out Lead Leukocytes Light Literature Maintenance MicroRNAs Middle Cerebral Artery Occlusion Modeling Morbidity - disease rate Multiple Sclerosis Neuraxis Neurologic Neurologic Deficit Neurological outcome Neutrophil Infiltration Oxygen Parkinson Disease Participant Pathogenesis Patients Pericytes Permeability Phase Physiology Plasminogen Activator Play Prevention Process Property Proteins Publishing RANTES RNA Interference Rattus Regulation Regulator Genes Reperfusion Injury Reperfusion Therapy Reporting Role Secondary to Site Stroke System Technology Testing Therapeutic Tight Junctions Transfection Traumatic Brain Injury Umbilical vein Vascular Dementia Vascular Diseases Work alternative treatment attenuation base blood-brain barrier permeabilization brain endothelial cell cerebral microvasculature cytokine deprivation endothelial dysfunction experimental study gene therapy hnRNP A1 improved in vitro Model in vivo in vivo Model in vivo monitoring innovation intravital microscopy migration monocyte mortality nervous system disorder neuroinflammation neurovascular novel overexpression post stroke prevent recruit response restoration stroke model stroke outcome systemic inflammatory response therapeutic development tool trafficking treatment strategy

项目摘要

It has been recognized that blood brain barrier (BBB) dysfunction exists in most neurological diseases, including stroke, multiple sclerosis, Alzheimer's and Parkinson's diseases, brain infections and epilepsy. Inflammation plays a significant role in BBB injury, secondary to pro-inflammatory factors produced in the brain or blood and leukocyte engagement of brain endothelium. Brain microvascular endothelial cells (BMVEC) are active participants and regulators of inflammatory processes at a site of inflammation. Inflammatory responses in brain endothelium involve hundreds of genes whose expression requires fine-tuned regulation. microRNAs (miRNAs) recently emerged as major regulators of gene expression. Very limited information exists about their participation in inflammatory responses caused by ischemia/reperfusion (I/R) events in brain endothelial cells. We propose to investigate the role of miRNAs in brain endothelium using well-established in vitro systems for functional studies of the BBB and imaging of brain microvasculature in an in vivo model of neuroinflammation. Based on our studies of BBB dysfunction during neuroinflammation, we propose that barrier protection is best achieved when the intervening agents possess anti-inflammatory properties and can stabilize tight junctions. Recently we have identified highly modified miRNAs, belonging to the let-7 miRNA family, which are important for endothelial maintenance. let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2, CCL5, IL8 and IP10/CXCL10. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across brain endothelium and diminished expression of pro-inflammatory cytokines. In oxygen glucose deprivation (OGD) followed by reperfusion (OGD/R), an in vitro I/R model, overexpression of these miRNAs led to increased BBB tightness, thereby attenuating barrier `leakiness'. Overexpression of these miRNAs resulted in decreased infarct volume and neutrophil infiltration in the brain in tMCAO, an in vivo I/R stroke animal model. In our proposed study, we will test the overexpression or inhibition of selected miRNAs on BBB tightness and leukocyte-endothelial cell engagement (adhesion/migration). Using bioinformatics, we will identify other targets for miRNAs. Next, we will perform miRNA transfection in vivo and monitor how the presence of miRNAs will change leukocyte adhesion/migration in an animal model of stroke. Proposed experiments will provide identification and functional assessment of miRNAs in brain endothelium, and lead to future therapeutic developments for prevention of deleterious effects of ischemia/reperfusion on the brain.

人们已经认识到，血脑屏障（BBB）功能障碍存在于大多数神经系统疾病中，