Plasminogen activators and cerebral ischemic injury

描述（由申请人提供）：由于中风或分娩或分娩后呼吸管理问题，婴儿在围产期经常暴露于缺氧和缺血。新生儿中风的发病率可高达1/4000。脑血管功能障碍是神经系统损伤的一个原因。FDA唯一批准的治疗急性中风的方法是给予tPA。然而，在基础科学研究中，已经观察到tPA表现出有益/有害的双重作用。除了在再灌注中的有益作用外，tPA还可能导致神经元细胞死亡。tPA治疗性治疗悖论的一个潜在解释可能与tPA的血管活性（扩张）有关。术语神经血管单位（NVU）关注脑血管和神经元之间的相互作用。有丝分裂原活化蛋白激酶（MAPK）表达增强脑缺血后，可能是影响血管和基因组学的最远端系统之一。假设是脑缺氧/缺血后纤溶酶原激活物的产生导致脑血流动力学受损和损伤后神经元细胞丢失。假设纤溶酶原激活剂损害对血管刺激的反应性并产生充血，其导致水肿，引起神经元细胞损失。因此，脑血管和神经元之间的动态相互作用导致对损伤的综合反应，与NVU概念一致。为了解决这一假设，将在新生猪中追求三个具体目标：1.探讨纤溶酶原激活物与缺氧缺血后脑血流动力学的关系。研究MAPK作为纤溶酶原激活剂控制脑血流动力学损伤后的机制的作用; MAPK亚型表达谱的变化导致脑血流动力学受损和神经元细胞丢失。3.确定损伤后脑血流动力学受损与组织病理学之间的相关性。将使用闭合颅窗技术测量软脑膜动脉直径，并通过ELISA测定CSF纤溶酶原激活剂浓度。CBF将通过放射性标记微球法测定。免疫组织化学和技术检测纤溶酶原激活剂和MAPK表达将被用来实现一个完整的动物/分子的观点之间的关系纤溶酶原激活剂，脑血流动力学和组织病理学。

DESCRIPTION (provided by applicant): Babies are frequently exposed to hypoxia and ischemia during the perinatal period due to stroke or problems with delivery or respiratory management post delivery. Neonatal stroke incidence can be as high as 1 in 4000 births. One contributor to neurologic damage is cerebrovascular dysfunction. The only FDA approved treatment for acute stroke is the administration of tPA. Nonetheless, in basic science studies, tPA has been observed to exhibit a dual beneficial/deleterious effect. In addition to its salutary role in reperfusion, tPA may contribute to neuronal cell death. A potential explanation for the tPA therapeutic treatment paradox could relate to the vascular activity (dilation) of tPA. The term neurovascular unit (NVU) focuses attention on the interactions between cerebral blood vessels and neurons. Mitogen activated protein kinase (MAPK) expression is enhanced after cerebral ischemia and may be one of the most distal systems affecting both the vasculature and genomics. The hypothesis is that plasminogen activator production following cerebral hypoxia/ischemia contributes to impaired cerebral hemodynamics and neuronal cell loss post insult. Plasminogen activators are hypothesized to impair reactivity to vascular stimuli and produce hyperemia which results in edema causing neuronal cell loss. Dynamic interactions between cerebral blood vessels and neurons thus result in an integrated response to the insult, consistent with the NVU concept. To address this hypothesis, three specific aims will be pursued in newborn pigs: 1. Characterize the relationship between plasminogen activators and cerebral hemodynamics after hypoxia/ischemia, 2. Investigate the role of MAPK as the mechanism by which plasminogen activators control cerebral hemodynamics post insult; Changes in the MAPK isoform expression profile result in impaired cerebral hemodynamics and neuron cell loss. 3. Determine the association between impaired cerebral hemodynamics and histopathology post insult. The closed cranial window technique will be used to measure pial artery diameter and determine CSF plasminogen activator concentration via ELISA. CBF will be determined by the radiolabeled microsphere method. Immunohistochemistry and techniques for detection of plasminogen activator and MAPK expression will be used to achieve an integrated whole animal/molecular perspective on the relationship between plasminogen activators, cerebral hemodynamics, and histopathology.