Hemorrhage Induced Brain Injury

脑出血（ICH）是一种毁灭性的中风。脑出血引起的脑损伤是由于 不断增长的血肿和血块形成，通过水肿和细胞凋亡损害邻近的大脑。 虽然这些是ICH后发生的不同病理实体，但我们有数据表明它们有一些共同之处。 共同机制。我们发现血肿周围脑细胞凋亡部分是由谷氨酸介导的 兴奋性毒性这使我们找到了非受体酪氨酸激酶pp 60-Src（Src），因为它增强了 NMDA受体通过NR 2A亚基的直接磷酸化。我们发现Src激酶活性 在大鼠实验性ICH后增加4倍，Src家族激酶（SFK）成员林恩增加超过 21倍，并且Src抑制剂减少细胞凋亡并改善ICH后的行为结果。 我们假设Src在脑出血介导的细胞凋亡和水肿中起核心作用： Src受体激活，激活NR 2A亚基，介导细胞凋亡; ICH激活凝血酶 通过Src激活HIF和MMPs受体，从而产生水肿和不良行为结果。这些 假设是基于先前的研究，表明凝血酶介导急性脑水肿 在ICH后，凝血酶通过凝血酶受体激活Src。这些研究将 检查：（a）ICH对Src的影响;（B）凝血酶对Src的激活;（c）ICH诱导的Src的磷酸化。 Src对NMDA受体的影响;（d）Src对HIF-1、HIF-1靶基因和MMP的激活;以及（e）Src对HIF-1受体的影响。 阻断对脑出血大鼠模型的细胞存活、水肿和行为结果的影响 （ICH）。将实现以下目标：目标#1a-d：证明Src mRNA、Src蛋白、Src 磷酸化和Src活性在ICH后增加。确定凝血酶拮抗剂是否阻断 这些ICH诱导的Src变化以及凝血酶和凝血酶受体激动剂是否再现ICH 诱导Src的变化。目标2。证明HIF-1、HIF-1靶基因VEGF和 脑出血后基质金属蛋白酶与NMDA受体亚单位磷酸化状态的变化 并且没有Src的药理学阻断。目标3。证明Src的药理学抑制 改善大鼠ICH后的细胞存活、减少脑水肿和改善行为结果（a） 使用ICH的血液输注模型和（B）使用ICH的缝合诱导的血管破裂模型。

Intracerebral hemorrhage (ICH) is a devastating stroke. The damage that occurs in brain from ICH is due to the growing hematoma and clot formation that damages the adjacent brain through edema and apoptosis. Though these are distinct pathologic entities that occur following ICH, we have data that they share some common mechanisms. We found that apoptosis in peri-hematoma brain is mediated in part by glutamate excitotoxicity. This led us to the non-receptor tyrosine kinase, pp60-Src (Src) because it potentiates function of NMDA receptors through direct phosphorylation of the NR2A subunit. We found that Src kinase activity increases 4 fold following experimental ICH in rats, the Src family kinase (SFK) member Lyn increases over 21 fold following ICH, and Src inhibitors decrease apoptosis and improve behavioral outcome following ICH. We hypothesize that Src plays a central role in ICH mediated apoptosis and edema: ICH causes thrombin receptor activation of Src that activates NR2A subunits that mediate apoptosis; and ICH activates thrombin receptors which activates HIF and MMPs via Src to produce edema and poor behavioral outcome. These hypotheses are based upon previous studies showing that thrombin mediates the acute brain edema following ICH, and that thrombin activates Src via the thrombin receptor. Therefore, these studies will examine: (a) the effect of ICH on Src; (b) thrombin activation of Src; (c) ICH induced phosphorylation of NMDA receptors by Src; (d) Src activation of HIF-1, HIF-1 target genes and MMPs; and (e) the effect of Src blockade on cell survival, edema and behavioral outcome using rat models of intracerebral hemorrhage (ICH). The following aims will be addressed: Aims #1a-d: Demonstrate that Src mRNA, Src protein, Src phosphorylation and Src activity increase following ICH. Determine whether thrombin antagonists block these ICH induced changes of Src and whether thrombin and thrombin receptor agonists reproduce the ICH induced changes of Src. Aim #2. Demonstrate changes of HIF-1, of the HIF-1 target gene VEGF, and the Matrix Metalloproteinases and the phosphorylation state of NMDA receptor subunits after ICH in rats with and with out pharmacological blockade of Src. Aim #3. Demonstrate that pharmacological inhibition of Src improves cell survival, decreases brain edema and improves behavioral outcome following ICH in rats (a) using a blood infusion model of ICH and (b) using a suture induced vessel rupture model of ICH.