BBB protection during treatment of transient ischemia

描述(申请人提供)：血脑屏障(BBB)是维持脑内平衡和调节化合物在血和脑之间运动所必需的。血脑屏障的失效会导致脑肿胀，这与包括缺血性中风在内的许多脑损伤状态有关。血管生成素-1(Ang-1)可促进血管生成，抵抗血脑屏障渗漏。另一种新的转录因子Homebox D3(Hoxd3)通过诱导血管内皮细胞和平滑肌细胞的增殖和迁移，稳定血管生成，减少缺血/再灌注引起的血脑屏障破坏，促进血管生成。我们将从一个新的角度研究血脑屏障功能：脑损伤后的血脑屏障功能障碍是血管生成刺激引起的生理反应的一部分。因此，开发的治疗路线必须考虑更大规模的血脑屏障抗渗漏框架中的血管生成。我们假设，在再灌流早期协调给予Ang-1和在再灌流后期给予Hoxd3基因可促进受损小鼠脑内功能性血管生成；包括增加局部脑血流量，减少血脑屏障渗漏和水肿，重塑完整的血管壁，并改善神经预后。我们将首先确定Ang-1是否在再灌注的早期阶段(2-48小时)增加连接蛋白的表达(闭锁带和claudin-1)，并减少血脑屏障的渗漏。然后，我们将确定使用血管生成因子Hoxd3是否能促进再灌注后期(3至28天)的功能性血管生成。进一步，我们将探讨Ang-1和Hoxd3在减少血脑屏障渗漏的情况下诱导血管生成的机制。我们提出了一个以治疗为导向的研究计划，以操纵脑损伤后的血管生成。具体地说，我们寻求平衡血管生成的血脑屏障可塑性的前期修复和必要的诱导，而不会受到屏障完整性丧失的不利影响。通过一种新的小鼠tMCAO模型和TAT蛋白输送技术，我们希望开发出特异性的治疗方法来减少与再灌注相关的血脑屏障渗漏，并通过促进功能性血管生成来减少缺血/再灌注脑损伤。

DESCRIPTION (provided by applicant): The Blood Brain Barrier (BBB) is essential for brain homeostasis and regulating the movement of compounds between blood and brain. Failure of the BBB leads to cerebral swelling, which is involved in many brain injury states including ischemic stroke. Angiopoietin-1 (Ang-1) has been shown to promote angiogenesis resistant to BBB leakage. Another novel transcription factor, Homebox D3 (HOXD3) promotes angiogenesis by inducing endothelial and smooth muscle cell proliferation and migration, stabilizing angiogenesis, and reducing ischemia/reperfusion induced BBB disruption. We will study BBB function from a novel perspective: BBB dysfunction after cerebral injury is part of the physiological repertoire of responses that result from stimulation of angiogenesis. As such, developing lines of therapy must consider angiogenesis in the larger scale BBB leakage resistance framework. We hypothesize that orchestrated administration of Ang-1 in the early stages of reperfusion and HOXD3 gene in the later stages of reperfusion promote functional angiogenesis in the injured mouse brain; including increased local CBF, reduced BBB leakage and edema, remodeled intact vessel walls, and improved neurological outcomes. We will first determine if Ang-1 increases junction protein expression (zonula occludens and claudin-1), and attenuates BBB leakage in the early stages (2 to 48 h) of reperfusion. We will then determine whether using an angiogenic factor, HOXD3, promotes functional angiogenesis during the late stages (3 to 28 d) of reperfusion. Further, we will explore the mechanism by which Ang-1 and HOXD3 induce angiogenesis with less BBB leakage. We propose a therapy-oriented research plan to manipulate angiogenesis after cerebral injury. Specifically, we seek to balance the prorepair and necessary induction of BBB plasticity for angiogenesis without the adverse effect of barrier integrity loss. With a novel mouse tMCAO model and TAT-protein delivery technique, we expect to develop specific therapies to attenuate BBB leakage associated with reperfusion, and to decrease ischemia/reperfusion brain damage by accelerating functional angiogenesis.