Neuroprotection of Erythropoietin Signaling in TBI

项目4：促红细胞生成素信号在脑损伤中的神经保护作用 脑低灌注量在脑挫伤后的损伤中起一定作用。如果CBF的减少 如果病情足够严重，就会出现脑缺血损伤。如果CBF的减少不够严重，不足以导致 氧气耗尽，那么基线低流量会导致脑组织更容易发生继发性 对缺血儿的侮辱。这两种情况都对神经学结果有公认的不利影响。 在皮质撞击损伤模型中，脑挫伤的脑低灌注率与其亲属 内皮型一氧化氮合酶(ENOS)引起的一氧化氮(NO)缺乏。和 应用L精氨酸(eNOS的底物)或四氢生物蝶呤(AN 内皮型一氧化氮合酶导致脑内NO浓度升高并恢复脑血流量 挫伤的大脑恢复到受伤前的水平。精氨酸改善脑挫伤后血流灌注的实验研究 与挫伤体积的减少有关。 促红细胞生成素(EPO)在损伤后在大脑中表达，并具有几种可能是 具有神经保护作用。大量研究表明，EPO可上调一氧化氮合酶或增加一氧化氮 产生或扩张血管的方式表明血管内皮细胞不产生。在生理上 内源性促红细胞生成素增加的情况，如在高海拔地区训练的运动员， NO的产量也有所增加。最后，在某些病理情况下，EPO给药已经 可以扩张脑血管。在蛛网膜下腔出血模型中，EPO逆转血管收缩 发生在颅内血管中。单剂量的促红细胞生成素已被证明可以保护自律性 蛛网膜下腔出血后的脑血流。 本研究旨在探讨促红细胞生成素对脑缺血再灌注损伤的神经保护作用机制。 创伤后发生的血管功能障碍。研究脑损伤后EPO及EPO受体(EPOR)的表达。研究促红细胞生成素信号增强对脑血流动力学的急性影响。目的：研究EPO信号增强对脑损伤反应的慢性影响。 目的：研究EPO和EPOR多肽对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.