Angiogenesis, Functional Recovery and TNF-alpha after Stroke

描述（由申请人提供）：除了细胞保护外，促进缺血后血管生成和功能恢复已成为治疗中风的潜在方法。肿瘤坏死因子受体- α (tnf - α)和核因子κ B （NF-(B)）在许多病理和生理事件中发挥重要作用，包括阻断细胞凋亡和促进血管生成。然而，TNF-(- nf -(B)级联的这两种作用在缺血脑中尚未得到很好的定义。基于前期和前期实验，我们提出验证TNF-(- nf -(B)通路介导的抗凋亡作用和血管生成促进小灶性脑皮质神经血管重构和功能恢复的假设。这种独特的中风模型将在野生型小鼠和缺乏TNF-受体TNFR1 （p55）、TNFR2 （p75）或NF- κ B p50的基因敲除小鼠中进行测试，这将使我们能够在被临床上重要的小中风选择性损伤的须-桶通路的明确定义的感觉-运动皮层的病理和功能变化的背景下检查TNF-(-NF- B)级联。目的1。桶状皮质脑卒中后TNF-(- nf -(B)级联抗凋亡作用。我们假设TNF-(- nf -(B)通路对神经元和血管内皮细胞缺血诱导的凋亡具有保护作用。选择性消除和改变TNFR1、TNFR2和NF-(B)信号对细胞凋亡的影响将在局灶性缺血后评估。目标2。桶状皮质脑卒中后TNF-(- nf -(B)级联刺激血管生成。我们将研究TNF-(- nf -(B)通路参与增加血管生成信号的可能性，如血管内皮生长因子（VEGF）和血管生成素，促进缺血后血管生成。我们还将检验这样一个假设，即通过调节血管生成活动可以避免致癌等负面后果。目标3。脑桶皮质卒中后TNF-(- nf -(B)级联促进功能恢复。预计TNF-(- nf -（B -级联）诱导的细胞存活和血管生成可促进脑桶皮质卒中后神经血管的可塑性和长期功能恢复。这些事件之间的因果关系将在野生型和基因敲除小鼠中通过阻断和刺激在Aim 1和2中识别的信号来评估。

DESCRIPTION (provided by applicant): In addition to cell protection, promoting post-ischemic angiogenesis and functional recovery has emerged as a potential approach for the treatment of stroke. Tumor necrosis factor receptor- alpha( (TNF-alpha) and nuclear factor kappa B (NF-(B) play critical roles in many pathological and physiological events including blocking apoptosis and promoting angiogenesis. These two actions of the TNF-(-NF-(B cascade, however, have not been well defined in the ischemic brain. Based on previous and preliminary experiments, we propose to test the hypothesis that the TNF-(-NF-(B pathway-mediated anti-apoptotic effect and angiogenesis promote neurovascular remodeling and functional recovery after a small focal ischemia in the barrel cortex. This unique stroke model to be tested in wild type mice and gene-knockout mice lacking TNF-( receptor TNFR1 (p55), TNFR2 (p75), or NF- kappa B p50 will allow us to examine the TNF-(-NF-(B cascade in the context of pathological and functional changes in the well-defined sensory-motor cortex of the whisker-barrel pathway selectively damaged by the clinically important small stroke. Aim 1. Anti-apoptotic effects of the TNF-(-NF-(B cascade after barrel cortex stroke. We hypothesize that the TNF-(-NF-(B pathway is protective against ischemia-induced apoptosis in neurons and vascular endothelial cells. The effects of selectively eliminating and changing TNFR1, TNFR2, and NF-(B signals on apoptosis will be evaluated after the focal ischemia. Aim 2. Angiogenesis stimulated by the TNF-(-NF-(B cascade after barrel cortex stroke. We will examine the possibility that the TNF-(-NF-(B pathway is involved in increasing angiogenic signals such as vascular endothelial growth factor (VEGF) and angiopoietins that promote angiogenesis after ischemia. We will also test the hypothesis that negative consequences such as carcinogenesis can be averted by modulating angiogenic activity. Aim 3. Functional recovery promoted by the TNF-(-NF-(B cascade after barrel cortex stroke. It is expected that TNF-(-NF-(B -cascade-induced cell survival and angiogenesis promote neurovascular plasticity and long-term functional recovery after the barrel cortex stroke. The cause-effect relationship between these events will be evaluated in wild type and gene-knockout mice by blocking and stimulating the signals identified in Aim 1 and 2. This investigation aims to elucidate the relationship between the TNF-(-NF-(B cascade, apoptosis, and angiogenesis, and functional recovery after a small ischemic stroke that represents 38% of clinical cases. Results from this study are expected to provide novel strategies for promoting functional restoration after focal ischemic stroke.