Mechanisms of thrombin-induced tolerance to brain injury

超出所提供的空间。 脑出血（ICH）是一种常见且往往致命的中风亚型，并在幸存者中产生严重的神经功能缺损。脑出血后的脑损伤似乎涉及几个阶段。这些包括涉及凝血级联和凝血酶产生的早期阶段和涉及红细胞溶解和血红蛋白毒性的后期阶段。虽然高浓度的凝血酶会导致脑水肿和细胞死亡，但低浓度的凝血酶具有神经保护作用。因此，我们已经发现，在大鼠大脑中动脉闭塞模型中，预先用低剂量凝血酶治疗可减弱凝血酶或出血诱导的脑水肿，并显著减小梗死面积。我们称这种现象为凝血酶预处理（TPC）。在我们最近的研究中，我们发现TPC不仅减少由高剂量凝血酶诱导的脑水肿，而且减轻由溶解的红细胞和FeCl 2诱导的水肿。TPC似乎涉及凝血酶受体的活化、HIF-1c上调和增加的转铁蛋白、转铁蛋白受体和铁蛋白水平。这表明在ICH期间凝血酶释放可能诱导针对凝块溶解时释放的因子的保护机制。这些数据使我们达到了以下具体目的：1）确定TPC是否减少由红细胞溶解引起的出血性脑损伤。 2)确定蛋白酶激活受体（PAR）是否在TPC中起关键作用。 3)确定TPC是否调节脑内铁转运和储存蛋白水平，进而影响ICH后铁稳态。 我们的项目的目的是研究TPC涉及的机制。检查TPC也将有助于我们理解缺血预适应，因为初步数据表明，TPC是该现象的一个组成部分。应该注意的是，TPC似乎是受体介导的，与缺血预处理相比，大大方便了分析。这些研究的长期目标是找到可用于限制ICH后脑损伤的机制。性能现场=

EXCEED THE SPACE PROVIDED. Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke and produces severe neurologic deficits in survivors. Brain injury after ICH appears to involve several phases. These include an early phase involving the clotting cascade and thrombin production and a later phase involving erythrocyte lysis and hemoglobin toxicity. Although high concentrations of thrombin cause brain edema and cell death, low concentrations are neuroprotective. Thus, we have found that prior treatment with a low dose of thrombin attenuates the brain edema induced by thrombin or hemorrhage, and significantly reduces the infarct size in a rat middle cerebral artery occlusion model. We have termed this phenomenon thrombin preconditioning (TPC). In our recent studies, we have found that TPC not only reduces brain edema induced by high dose thrombin, but also attenuates edema induced by lysed erythrocytes and FeCI2. TPC appear to involve activation of thrombin receptor, HIF-lc_ upregulation and increased transferrin, transferrin receptor and ferritin levels. This suggests that thrombin release during an ICH might induce protective mechanisms against factors released upon clot lysis. This data has led us to the following specific aims: 1) To determine whether TPC reduces hemorrhagic brain injury caused by lysis of erythrocytes. 2) To determine whether protease-activated receptors (PARs) play a key role in TPC. 3) To determine whether TPC modulates iron transport and storage protein levels in the brain, which then affects iron homeostasis after ICH. The purpose of our project is to investigate the mechanisms involved in TPC. An examination of TPC will also help our understanding of ischemic preconditioning since preliminary data suggests that TPC is a component of that phenomenon. It should be noted that TPC seems to be receptor mediated, greatly facilitating analysis compared to ischemic preconditioning. The long term goal of these studies is to find mechanisms that can be used to limit brain injury after ICH. PERFORMANCE SITE ========================================Section End===========================================