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

点击翻译按钮获取中文摘要

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.