Plasminogen activators and cerebral ischemic injury

描述(申请人提供)：婴儿在围产期经常因中风或分娩或产后呼吸管理问题而暴露于缺氧和缺血中。新生儿中风的发病率可能高达每4000名新生儿中就有一名。导致神经损伤的一个因素是脑血管功能障碍。FDA批准的治疗急性中风的唯一方法是给予tPA。尽管如此，在基础科学研究中，tPA已被观察到具有双重的有益和有害的影响。除了在再灌流中的有益作用外，tPA还可能导致神经细胞死亡。TPA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)关注的是脑血管和神经元之间的相互作用。丝裂原活化蛋白激酶(MAPK)在脑缺血后表达增强，可能是影响血管系统和基因组学的最远端系统之一。假设脑缺氧/缺血后产生纤溶酶原激活剂，导致脑血流动力学受损和损伤后神经细胞丢失。纤溶酶原激活剂被认为会削弱对血管刺激的反应性，并产生充血，导致水肿，导致神经细胞丢失。因此，脑血管和神经元之间的动态相互作用导致了对侮辱的综合反应，这与NVU的概念一致。为了解决这一假说，将在新生猪身上寻求三个特定的目标：1.表征缺氧/缺血后纤溶酶原激活物与脑血流动力学的关系；2.探讨MAPK作为纤溶酶原激活物控制损伤后脑血流动力学的机制；MAPK亚型表达谱的变化导致脑血流动力学受损和神经细胞丢失。3.确定脑血流动力学受损与伤后组织病理学的关系。采用封闭式颅窗技术测量软脑膜动脉内径，用ELISA法测定脑脊液纤溶酶原激活物浓度。CBF将用放射性标记微球法测定。将利用免疫组织化学和纤溶酶原激活物和MAPK表达的检测技术，实现对纤溶酶原激活剂、脑血流动力学和组织病理学之间关系的整体动物/分子观点。

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.