Hemorrhage Induced Brain Injury

出血引起的脑损伤

• 批准号: 7337071
• 负责人: FRANK R SHARP
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337071
• 关键词: Acute; Address; Affect; Agonist; Apoptosis; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Cell Death; Cell Survival; Cerebral hemisphere hemorrhage; Coagulation Process; Data; Development; Edema; Gene Targeting; Glutamates; Hematoma; Hemorrhage; Hemostatic function; Hypoxia Inducible Factor; Infusion procedures; Injection of therapeutic agent; Injury; Intervention; Lead; Matrix Metalloproteinases; Mediating; Messenger RNA; Modeling; N-Methyl-D-Aspartate Receptors; Neurologic; Outcome; Pathologic; Pathology; Patients; Phosphorylation; Play; Proteins; Rattus; Receptor Activation; Receptor Protein-Tyrosine Kinases; Research Personnel; Role; Rupture; SRC gene; Societies; Stroke; Surgical sutures; Thrombin; Thrombin Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; base; excitotoxicity; improved; inhibitor/antagonist; member; mortality; prevent; programs; src-Family Kinases

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.

脑内出血（ICH）是毁灭性的中风。 ICH大脑中发生的损害是由于 通过水肿和凋亡损害相邻大脑的血肿和凝块形成的增长。 尽管这些是ICH之后发生的不同病理实体，但我们有数据可以共享一些 通用机制。我们发现，谷氨酸部分介导了血肿大脑的凋亡 兴奋性毒性。这使我们进入了非受体酪氨酸激酶PP60-SRC（SRC），因为它增强了功能 NR2A亚基的直接磷酸化，NMDA受体的成绩。我们发现SRC激酶活性 在大鼠实验ICH后增加4倍，SRC家族激酶（SFK）成员Lyn增加 ICH之后的21倍和SRC抑制剂可降低凋亡并改善ICH之后的行为结果。 我们假设SRC在ICH介导的凋亡和水肿中起着核心作用：ICH会导致凝血酶 激活介导凋亡的NR2A亚基的SRC的受体激活； ICH激活凝血酶 通过SRC激活HIF和MMP的受体可产生水肿和行为不良结果。这些 假设基于以前的研究表明凝血酶介导急性脑水肿 遵循ICH，该凝血酶通过凝血酶受体激活SRC。因此，这些研究将 检查：（a）ICH对SRC的影响； （b）SRC的凝血酶激活； （c）ICH诱导的磷酸化 SRC的NMDA受体； （d）HIF-1，HIF-1靶基因和MMP的SRC激活； （e）SRC的影响 使用脑出血的大鼠模型对细胞存活，水肿和行为结果的封锁 （ICH）。将解决以下目标：目标＃1A-D：证明SRC mRNA，SRC蛋白，SRC ICH后，磷酸化和SRC活性增加。确定凝血酶拮抗剂是否阻塞 这些ICH引起的SRC的变化以及凝血酶和凝血酶受体激动剂是否繁殖ICH 诱导SRC的变化。目标＃2。证明HIF-1，HIF-1靶基因VEGF的变化和 基质金属蛋白酶和NMDA受体亚基的磷酸化状态ICH在大鼠中 并与SRC的药理学封锁。目标＃3。证明药理学抑制SRC 改善细胞存活，减少脑水肿并改善大鼠ICH后的行为结果（a） 使用ICH的血液输注模型和（b）使用缝合诱导的血管破裂模型。