Novel Neuroprotective Roles for Neuregulins in the Trea*

Trea* 中神经调节蛋白的新神经保护作用

• 批准号: 7167397
• 负责人: BYRON D. FORD
• 金额: $ 7.1万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167397
• 关键词: Novel; Neuroprotective; Roles; Neuregulins; Trea

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)

描述（由申请人提供）： 中风是美国的第三大死亡原因，也是长期残疾的主要原因。但是，在缺血性中风的治疗过程中取得了很少的进步。因此，该项目的总体目标是开发和表征一种新型的中风神经保护疗法。神经结合蛋白与脑缺血后的正常脑功能以及神经保护作用有关。我们实验室的最新工作表明，在大鼠局灶性中风模型中，单轮内施用的单一低剂量（2.5 ng/kg）将缺血诱导的神经元死亡降低了〜90％，其治疗窗口至少为5.5小时。 NRG-1给药还导致神经功能的显着改善。神经保护与抑制细胞凋亡，星形胶质细胞增多症和白介素-1 mRNA表达有关。我们通过微阵列分析证明了NRG-1不仅阻止了白介素-1的表达，而且还削弱了缺血后促炎和应力基因表达的广泛模式。我们进一步表明，NRG-1使用培养的巨噬细胞直接阻断促炎基因表达。因此，我们假设NRG-1在调节局灶性中风后调节神经保护和炎症方面起着重要作用。因此，神经结合蛋白代表了一种新型的有效神经保护策略，该策略在急性缺血性中风后具有潜在的治疗价值。该项目的核心假设是神经调节蛋白是新型的神经保护剂，在缺血性中风后促进神经元存活和功能恢复，并具有扩展的治疗窗口。为了检验我们的假设，我们将采用以下一组具体目标： （1）检查缺血后NRG-1的剂量依赖性和同工型特异性神经保护作用，（2）确定缺血后NRG-1的神经保护作用所涉及的生理和药理机制（S），以及（3）确定NRG-1神经性的治疗窗口和长期效应。这项研究将使神经损伤中神经抑制蛋白的新颖而可能的关键作用给予新的见解。这里的这些研究具有巨大的临床潜力，并可能导致缺血性中风治疗的新治疗策略。 （抽象的结尾）