NEUROSCIENCE

脑缺血发生在向大脑的动脉血液供应被阻塞时，导致脑损伤或梗塞的区域。所产生的缺血性脑损伤伴随着神经元、神经胶质和脑血管中炎性分子、细胞因子和活性氧的合成增加。缺血和诱导的细胞因子均上调下游促炎分子的表达。对缺血性脑损伤的促炎反应与梗塞面积增加和神经学预后不良相关;因此阻断炎症的化合物可能用作治疗脑缺血的疗法。Neuregulin是一种结构上与表皮生长因子（EGF）相关的多营养生长因子。神经调节蛋白转录本已在神经元和脑血管中检测到，而其受体（erbB）主要在大脑皮层、海马、小脑和胆碱能核中的神经元中表达。来自我们实验室的初步数据表明，neuregulin抑制了皮质和皮质神经细胞培养物中精氨酸诱导的基因表达。 海马神经元最近的一些报道暗示了神经调节蛋白在保护神经元免受脑损伤中的作用。Neuregulin减少实验性自身免疫性脑脊髓炎（EAE）小鼠模型中的炎症、促炎基因表达和脱髓鞘。神经调节蛋白及其受体在创伤性和机械性脑损伤的实验模型中显示出上调。在每种情况下，neuregulin和erbBs的诱导定位于病变边缘（半影）的细胞，表明neuregulin和erbBs在神经保护和修复中的作用。的特定角色相 神经调节蛋白在缺血性脑损伤中的作用尚未阐明。因此，我们将使用以下目的在啮齿动物脑缺血模型中检查神经调节蛋白和erbB受体诱导的潜在神经保护作用：（1）利用大鼠大脑中动脉闭塞（MCAO）模型研究神经调节蛋白或erbB受体的表达，（2）检测缺氧后培养的大鼠神经元细胞中neuregulin及其受体的表达;（3）研究neuregulin对基线的影响，缺氧和烟碱诱导炎症基因，并检测神经调节蛋白对皮层细胞的神经保护作用。这些研究将增加我们对neuregulin的了解，并可能导致新疗法的开发，这将改善急性斯托克治疗患者的临床结果。

Cerebral ischemia occurs when the arterial blood supply to the brain is obstructed, resulting in areas of brain damage or infarcts. The resulting ischemic brain injury is accompanied by the increased synthesis of inflammatory molecules, cytokines and reactive oxygen species in neurons, glia and in the cerebral vasculature. Both ischemia and the induced cytokines upregulate the expression of downstream proinflammatory molecules. The pro-inflammatory response to ischemic brain injury is associated with increased infarct size and poor neurological prognosis; therefore compounds that block inflammation are potentially useful as therapies to treat cerebral ischemia. Neuregulin is a pleitrophic growth factor structurally related to epidermal growth factor (EGF). Neuregulin transcripts have been detected in neurons and cerebral blood vessels while its receptors (erbBs) are expressed primarily in neurons in the cerebral cortex, hippocampus, cerebellum and cholinergic nuclei. Preliminary data from our laboratory demonstrate that neuregulin inhibits cytokine-induced gene expression in cultures of cortical and hippocampal neurons. Several recent reports have implicated a role for neuregulin in the protection of neurons against brain injury. Neuregulin decreased inflammation, pro-inflammatory gene expression and demyelination in a mouse model of experimental autoimmune encephalomyelitis (EAE). Neuregulin and its receptors were shown to be upregulated in experimental models of traumatic and mechanical brain injury. In each case, the induction of neuregulin and erbBs was localized to cells at the edge of the lesion (penumbra) suggesting a role for neuregulin and erbBs in neural protection and repair. A specific role for neuregulin in ischemic brain injury has not been elucidated. Therefore, we will examine the potential neuroprotective effect of neuregulin and erbB receptor induction in a rodent model of brain ischemia using the following aims: (1) Investigate the expression of neuregulin or erbB receptors ischemic brain injury using a rat middle cerebral artery occlusion (MCAO) model, (2) To examine the expression of neuregulin and its receptors by rat neuronal cells in culture following exposure to hypoxia and (3) Investigate the effects of neuregulin on baseline, hypoxia and cytokine-induced inflammatory gene in rat neuronal cultures and examine neuroprotective effects of neuregulin on cortical cells. These studies will increase our understanding of neuregulin and potentially lead to development of new therapies that will improve clinical outcomes among patients who are treated for acute stoke.