Targeting the Hippo signaling at the Blood-brain barrier for therapy of ischemic stroke

靶向血脑屏障的 Hippo 信号传导治疗缺血性中风

• 批准号: 10020445
• 负责人: Jiukuan Hao
• 金额: $ 34万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020445
• 关键词: Acute; Address; Affect; Area; Binding; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Ischemia; Cell Death; Cell Line; Cell Proliferation; Cell physiology; Cells; Cessation of life; Data; Development; Disease; Drug Delivery Systems; Endothelial Cells; Endothelium; Extravasation; Failure; Functional disorder; Glucose; Impairment; In Vitro; Inflammation; Inflammatory Response; Injury; Intracranial Pressure; Ischemia; Ischemic Stroke; Mesenchymal Stem Cells; Movement; Mus; Nature; Neuraxis; Neurons; Oxygen; Pathologic; Pharmaceutical Preparations; Pharmacology; Play; Preventive treatment; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; Transcription Coactivator; Vascular Endothelial Cell; angiogenesis; base; behavioral outcome; blood-brain barrier function; brain endothelial cell; cell type; clinical application; deprivation; drug discovery; exosome; improved; improved outcome; in vitro Model; in vivo; innovation; intravenous injection; ischemic injury; knock-down; migration; neurogenesis; new therapeutic target; novel; novel strategies; novel therapeutic intervention; overexpression; paralogous gene; protective effect; repaired; restoration; stroke outcome; stroke therapy; success; targeted delivery; targeted treatment; thrombolysis

Abstract Although considerable efforts have been made focusing on the neuronal/glial injury to find new targets for stroke therapy, no success has been achieved. Therapy of stroke is still limited to preventive treatments and to acute thrombolysis and symptomatic control of intracranial pressure. Pathological changes at the level of brain endothelium plays an important role in progression of brain diseases. However, the approaches to modulate the BBB function for therapy are still very limited. Recently, studies have shown that the YES-associated protein (YAP) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif), the transcriptional coactivators of the Hippo signaling pathway, promote endothelial cell proliferation, migration and angiogenesis. YAP/TAZ also plays a role in regulating formation and integrity of tight-junction, which indicates its possible role in tight-junction of the BBB. Our central hypothesis is that YAP/TAZ promotes brain angiogenesis and plays an important role in maintaining the BBB integrity, and YAP/TAZ-exosome has a therapeutic effect against brain ischemia/reperfusion injury by promoting repair of the BBB and restoration of the BBB integrity. The present proposal aims to elucidate the role of YAP/TAZ in regulating the BBB function, to evaluate protective effect of YAP/TAZ on brain ECs and the BBB against ischemia/reperfusion injury, and to develop a novel approach, YAP/TAZ-exosome, for treatment of ischemic stroke. We will use the ischemic stroke model in vitro and in vivo to test our hypothesis We expect that YAP/TAZ promotes brain ECs proliferation, migration and angiogenesis, and over- expression of YAP/TAZ and YAP/TAZ-Exosomes promote the BBB repair after ischemic injury, which leads to improvement of ischemic stroke outcomes shown as improved behavior outcome, less inflammatory responses and the BBB leakage in the brain etc. The proposed study is highly significant and innovative because it will advance our understanding of the role of YAP/TAZ in regulating the BBB function and pathophysiology of the BBB under ischemic stroke. The proposed project will explore YAP/TAZ as a novel therapeutic target for ischemic stroke therapy, exosome as a novel delivery carrier, and the brain EC as a novel site for brain disease therapy and brain drug delivery. Furthermore, the proposed therapeutic approach could be broadly applied for therapy of diseases affecting the BBB and central nervous system. Therefore, the overall impact of the project is highly significant in advancing drug discovery that targets the brain endothelium for brain disease therapy.

抽象的 尽管已经为关注神经元/神经胶质损伤而做出了巨大的努力，以寻找新的目标 中风疗法，无法取得成功。中风治疗仍然限于预防治疗和 急性溶栓和对颅内压的症状控制。大脑水平的病理变化 内皮在脑部疾病进展中起重要作用。但是，调制的方法 用于治疗的BBB功能仍然非常有限。最近，研究表明与YES相关 蛋白质（YAP）及其旁系同源物TAZ（带有PDZ结合基序的转录共激活因子），转录 河马信号通路的共激活剂，促进内皮细胞增殖，迁移和血管生成。 YAP/TAZ还在调节紧密结的形成和完整性中起作用，这表明其可能 在BBB的紧密结处中的作用。我们的中心假设是YAP/TAZ促进了脑血管生成和 在保持BBB完整性方面起着重要的作用，YAP/TAZ-Exosos具有治疗效果 通过促进BBB的修复和BBB完整性的恢复，可以抵抗脑缺血/再灌注损伤。 目前的建议旨在阐明YAP/TAZ在调节BBB功能中的作用，以评估 YAP/TAZ对脑EC和BBB的保护作用，以防止缺血/再灌注损伤，并发展 新颖的方法，YAP/TAZ-诊断，用于治疗缺血性中风。我们将在 体内和体内检验我们的假设 我们期望YAP/TAZ促进脑ECS的增殖，迁移和血管生成，并过度 YAP/TAZ和YAP/TAZ-诊断的表达促进缺血性损伤后的BBB修复，从而导致 表现为改善行为结果，炎症反应较少的缺血性中风结果的改善 大脑中的BBB泄漏等。拟议的研究非常重要且具有创新性，因为它将 促进我们对YAP/TAZ在调节BBB功能和病理生理学中的作用的理解 BBB低于缺血性中风。拟议的项目将探索YAP/TAZ作为新颖的治疗靶点 缺血性卒中疗法，外泌体作为一种新型递送载体，而大脑EC作为大脑的新地点 疾病疗法和脑部药物输送。此外，建议的治疗方法可以广泛 申请影响BBB和中枢神经系统的疾病治疗。因此， 该项目在推进针对脑内皮的药物发现方面非常重要 治疗。