Novel Neuroprotective Roles for Neuregulins in the Trea*

描述(由申请人提供)： 中风是美国第三大死亡原因，也是导致长期残疾的主要原因。然而，在开发缺血性中风的治疗方法方面进展甚微。因此，本项目的总体目标是开发和表征一种治疗中风的新型神经保护疗法。神经调节蛋白与正常的大脑功能以及脑缺血后的神经保护有关。我们实验室最近的工作表明，在大鼠局灶性卒中模型中，单一、低剂量(2.5 ng/kg)动脉内注射神经调节蛋白-1(NRG-1)可使缺血诱导的神经元死亡减少约90%，治疗窗口至少为5.5小时。NRG-1治疗后神经功能也有明显改善。神经保护作用与抑制细胞凋亡、星形胶质细胞增生和白介素1mRNA的表达有关。我们已经通过基因芯片分析证明，NRG-1不仅阻断了白细胞介素1的表达，而且还减弱了缺血后广泛存在的促炎和应激基因的表达模式。我们进一步表明，NRG-1通过培养巨噬细胞直接阻断了促炎基因的表达。因此，我们假设NRG-1在调控局灶性卒中后的神经保护和炎症方面发挥重要作用。因此，神经调节蛋白代表了一种新的、有效的神经保护策略，在治疗急性缺血性中风后的个体方面具有潜在的治疗价值。该项目的中心假设是，神经调节素是一种新型的神经保护剂，可以通过延长治疗窗口来促进缺血性中风后神经元的存活和功能恢复。为了验证我们的假设，我们将采用以下一组具体目标： (1)研究NRG-1的剂量依赖性和异构体特异性的脑缺血保护作用；(2)探讨NRG-1参与脑缺血保护作用的生理药理机制(S)；(3)确定NRG-1脑缺血保护的治疗窗口和远期效应。这项研究将为神经调节蛋白在缺血性脑损伤中的新作用提供新的见解，甚至可能是关键作用。这些研究具有巨大的临床潜力，并可能导致治疗缺血性中风的新的治疗策略。(摘要结束)

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States and the major cause of long-term disability. However, very little progress has been made in the development of treatments for ischemic stroke. Therefore, the overall goal of this project is to develop and characterize a novel neuroprotective therapy for stroke. Neuregulins have been implicated in normal brain function, as well as in neuroprotection following cerebral ischemia. Recent work from our lab demonstrated that a single, low dose (2.5 ng/kg) of intra-arterially administered neuregulin-1 (NRG-1) reduced ischemia-induced neuronal death in a rat focal stroke model by ~90% with a therapeutic window of at least 5.5 hours. NRG-1 administration also resulted in a significant improvement of neurological function. The neuroprotection was associated with the inhibition of apoptosis, astrogliosis and interleukin-1 mRNA expression. We have demonstrated by microarray analysis, that NRG-1 not only blocked interleukin-1 expression, but also attenuated the widespread pattern of pro-inflammatory and stress gene expression following ischemia. We further showed that NRG-1 directly blocked pro-inflammatory gene expression using cultured macrophages. We therefore hypothesize that NRG-1 plays an important role in regulating both neuroprotection and inflammation following focal stroke. Thus, neuregulins represent a novel, potent neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke. The central hypothesis of this project is that neuregulins are novel neuroprotective agents that promote neuronal survival and functional recovery following ischemic stroke with an extended therapeutic window. To test our hypothesis, we will employ the following set of specific aims: (1) To examine the dose-dependent and isoform-specific neuroprotective effects of NRG-1 following ischemia, (2) To determine the physiological and pharmacological mechanism(s) involved in the neuroprotective effects of NRG-1 following ischemia and (3) determine the therapeutic window and long-term effects for NRG-1 neuroprotective in ischemia. This study will give new insight to a novel and perhaps pivotal role for neuregulins in ischemic brain injury. These studies herein have enormous clinical potential and could lead to new therapeutic strategies in the treatment of ischemic stroke. (End of Abstract)