Neuroprotection of Erythropoietin Signaling in TBI

项目4.促红细胞生成素信号通路在颅脑损伤中的神经保护作用 脑灌注不足在挫伤性脑损伤中起重要作用。如果脑血流量减少 足够严重时，就会出现脑缺血性损伤如果CBF的减少不足以引起 缺氧，那么基线低流量导致脑组织更容易受到继发性 缺血性损伤这两种情况都对神经系统结局有明确的不良影响。 在皮质撞击损伤模型中，挫伤脑的脑灌注不足与相对的 由内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）缺乏。和 给予L-精氨酸（eNOS的底物）或给予四氢生物蝶呤（一种抗肿瘤药物）， eNOS的必需辅因子）导致脑中NO浓度增加，并恢复脑血流量。 挫伤的大脑恢复到受伤前的水平左旋精氨酸对脑挫伤脑灌注的改善作用 与挫伤体积的减少有关。 促红细胞生成素（Epo）在损伤后在脑中表达，并且具有几种可能与脑损伤有关的活性。 神经保护大量研究表明，给予Epo可上调NOS或增加NO NO的产生或扩张血管的方式表明NO生产的内皮。生理 内源性Epo产生增加的情况，例如在高海拔训练的运动员中， NO的产生也增加。最后，在某些病理条件下， 能扩张脑血管在蛛网膜下腔出血模型中，Epo逆转了血管收缩， 发生在颅内血管单剂量的Epo已被证明可以保持 蛛网膜下腔出血后的脑血流量 本研究的目的是探讨促红细胞生成素对脑缺血再灌注损伤的神经保护机制。 创伤后出现的血管功能障碍具体目的如下：研究脑损伤后Epo及其受体（EpoR）的表达。 研究增强的Epo信号对脑血流动力学的急性影响。 研究增强的Epo信号对脑损伤反应的慢性影响。 研究Epo和EpoR肽给药对大脑损伤反应的协同作用。

PROJECT #4. Neuroprotection of Erythropoietin Signaling in TBI Cerebral hypoperfusion plays a role in the injury that develops in contused brain. If the reduction in CBF is severe enough, cerebral ischemic injury develops. If the reduction in CBF is not severe enough to cause oxygen depletion, then the baseline low flow causes the brain tissue to be more vulnerable to secondary ischemic insults. Both circumstances have a well established adverse effect on neurological outcome. In the cortical impact injury model, cerebral hypoperfusion in contused brain is associated with a relative deficiency of nitric oxide (NO) produced by the endothelial isoform of nitric oxide synthase (eNOS). And administration of L-arginine (the substrate for the eNOS) or administration of tetrahydrobiopterin (an essential cofactor of eNOS) results in an increase in the NO concentrations in the brain and restores CBF in the contused brain back to pre-injury values. The improvement in perfusion of the contused brain with Larginine is associated with a reduction in contusion volume. Erythropoietin (Epo) is expressed in the brain after injury, and has several activities that might be neuroprotective. Numerous studies suggest that Epo administration upregulates NOS or increases NO production or dilates vessels in a manner that suggests NO production by endothelium. In physiological circumstances where endogenous Epo production is increased, such as in athletes training at high altitudes, production of NO is also increased. Finally in some pathological conditions, Epo administration has been found to dilate cerebral vessels. In a subarachnoid hemorrhage model, Epo reversed the vasoconstriction that occurred in intracranial vessels. A single dose of Epo has been shown to preserve autoregulation of cerebral blood flow following subarachnoid hemorrhage. The purpose of this study is to investigate these potentially neuroprotective mechanisms of Epo on the vascular dysfunction that occurs after trauma. The specific aims include the following: To study the expression of Epo and Epo receptor (EpoR) by the injured brain. To study the acute effects of augmented Epo signaling on cerebral hemodynamics. To study the chronic effects of augmented Epo signaling on the brain's response to injury. To study the synergistic effects of Epo and EpoR peptide administration on the brain's response to injury.