Center for Brain Hemorrhage Research

描述(由申请者提供)：该计划项目赠款(PPG)将阐述在神经外科服务中看到的三种主要脑出血性疾病中，“扩大的神经血管单位”如何对损伤和假定的治疗做出反应。扩大的神经血管单位不仅包括内皮细胞、周细胞和星形胶质细胞，还包括神经血管单位的供血动脉和上游脑动脉以及动脉平滑肌细胞。扩张的神经血管单位对出血性脑损伤的反应不仅具有普遍性，而且具有独特的病理生理特征。在我们的PPG中，我们建议对三种主要的脑出血疾病，蛛网膜下腔出血(SAH)、脑内出血(ICH)和创伤性脑损伤(TBI)的啮齿动物模型进行横向比较研究。类似地，我们将在所有三种不同的出血性脑损伤模型中比较三种不同的治疗策略，如骨桥蛋白(OPN)、抗PDGF(格列卫)和AP-Cav(小窝)。根据现有文献，结合我们自己的初步观察，我们的假设是，在SAH/ICH/TBI模型中，存在围绕脑出血后扩大的神经血管单位的普遍但不同的损伤特征。我们进一步假设，针对基质蛋白OPN、PDGF受体和内皮小窝蛋白的三种不同的神经血管保护策略将通过不同的机制防止动脉平滑肌表型改变，提供神经血管保护以加强血脑屏障(BBB)的完整性，改善血管功能和减轻脑水肿。

DESCRIPTION (provided by applicant): This Program Project Grant (PPG) will address how an "expanded neurovascular unit" responds to injury and putative therapeutic treatment in three major brain hemorrhagic disorders seen in neurosurgery service. The expanded neurovascular unit includes not only endothelial cells, pericytes, and astrocytes but also the feeding and upstream cerebral arteries of the neurovascular unit and arterial smooth muscle cells. The responses of the expanded neurovascular unit to hemorrhagic brain injury may not only demonstrate universal but also distinct pathophysiological features. In our PPG we propose a horizontal comparative study in rodent models o f t h e three major brain hemorrhage disorders, subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and traumatic brain injury (TBI). Similarly we will compare three different treatment strategies such as osteopontin (OPN), anti-PDGF (Gleevec), and AP-Cav (caveolin) in all three distinct hemorrhagic brain injury models. Based upon existing literature combined with our own preliminary observations, our hypothesis is that there are universal but distinct features of injury encompassing the expanded neurovascular unit following brain hemorrhage in SAH/ICH/TBI models. We further hypothesize that three distinct neurovascular protection strategies targeting the matrix protein OPN, PDGF-receptors, and endothelial caveolin will prevent arterial smooth muscle phenotype changes, provide neurovascular protection to strengthen blood-brain barrier (BBB) integrity, improve vascular function and reduce brain edema via different mechanisms.