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

摘要 虽然已经在神经元/神经胶质损伤方面做出了相当大的努力来寻找新的靶点 中风的治疗，一直没有取得成功。中风的治疗仍然局限于预防性治疗和 急性溶栓和对症控制颅内压。脑水平的病理改变 血管内皮细胞在脑部疾病的进展中起着重要作用。然而，调制的方法 血脑屏障在治疗中的作用仍然非常有限。最近，研究表明，与YES相关的 蛋白质(YAP)及其伴生的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物，促进内皮细胞的增殖、迁移和血管生成。 YAP/TAZ还在调节紧密连接的形成和完整性方面发挥作用，这表明其可能 在血脑屏障紧密连接中的作用。我们的中心假设是YAP/TAZ促进脑血管生成和 在维持血脑屏障完整性方面起着重要作用，YAP/TAZ-exosome具有治疗作用 通过促进血脑屏障的修复，恢复血脑屏障的完整性，抗脑缺血再灌注损伤。 本提案旨在阐明YAP/TAZ在调节血脑屏障功能中的作用，以评估 YAP/TAZ对脑内皮细胞和血脑屏障的保护作用 治疗缺血性卒中的新方法，YAP/TAZ-exosome。我们将使用缺血性中风模型在 来检验我们的假说 我们期望YAP/TAZ促进脑内皮细胞的增殖、迁移和血管生成，并过度- YAP/TAZ和YAP/TAZ-exosome的表达促进缺血损伤后的BBB修复，从而导致 缺血性卒中结果的改善表现为行为结果的改善，炎症反应的减少 以及脑内血脑屏障渗漏等。这项拟议的研究具有非常重要的意义和创新性，因为它将 进一步了解YAP/TAZ在调节血脑屏障功能和高血压病患者中的作用 缺血性卒中时的血脑屏障。拟议的项目将探索YAP/TAZ作为一种新的治疗靶点 缺血性卒中治疗，外切体作为新的递送载体，脑内皮细胞作为脑的新部位 疾病治疗和脑部药物输送。此外，拟议的治疗方法可以广泛应用于 用于治疗影响血脑屏障和中枢神经系统的疾病。因此，从总体上看， 该项目对促进针对脑部疾病的脑内皮细胞的药物发现具有重要意义。 心理治疗。

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.