BBB protection during treatment of transient ischemia

描述（由申请人提供）：血脑屏障（BBB）对于脑稳态和调节血液与脑之间化合物的运动至关重要。血脑屏障的衰竭导致脑肿胀，这涉及许多脑损伤状态，包括缺血性中风。血管生成素-1（Angiopoietin-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（HOXD 3）通过诱导内皮和平滑肌细胞增殖和迁移、稳定血管生成和减少缺血/再灌注诱导的BBB破坏来促进血管生成。我们将从一个新的角度研究血脑屏障功能：脑损伤后血脑屏障功能障碍是刺激血管生成引起的生理反应的一部分。因此，开发治疗线必须在更大规模的BBB渗漏抵抗框架中考虑血管生成。我们假设，在再灌注早期阶段协调给予Ang-1和在再灌注后期阶段协调给予HOXD 3基因促进损伤小鼠脑中的功能性血管生成;包括增加局部CBF，减少BBB渗漏和水肿，重塑完整的血管壁，改善神经功能结局。我们将首先确定Ang-1是否增加连接蛋白表达（闭锁小带和claudin-1），并在再灌注早期（2至48小时）减弱BBB渗漏。然后，我们将确定是否使用血管生成因子，HOXD 3，促进功能性血管生成在再灌注后期（3至28天）。此外，我们将探索Ang-1和HOXD 3诱导血管生成的机制，同时减少BBB泄漏。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。具体来说，我们寻求平衡的前修复和必要的诱导血脑屏障可塑性血管生成没有屏障完整性损失的不利影响。我们希望通过一种新的小鼠tMCAO模型和TAT蛋白递送技术，开发特异性治疗方法来减轻与再灌注相关的BBB渗漏，并通过加速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.