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）： 中风是美国第三大死亡原因，也是长期残疾的主要原因。然而，在缺血性卒中的治疗方面进展甚微。因此，本项目的总体目标是开发和表征一种新的脑卒中神经保护疗法。神经调节蛋白与正常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，单次低剂量（2.5 ng/kg）动脉内给予神经调节蛋白-1（NRG-1）可将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给药也导致神经功能的显著改善。神经保护作用与抑制细胞凋亡、星形胶质细胞增生和白细胞介素1 mRNA表达有关。我们已经通过微阵列分析证明，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促炎和应激基因表达的广泛模式。我们进一步表明，NRG-1直接阻断促炎基因表达使用培养的巨噬细胞。因此，我们假设NRG-1在调节局灶性卒中后的神经保护和炎症中起重要作用。因此，neuregulins代表了一种新的，有效的神经保护策略，在治疗急性缺血性卒中后的个体中具有潜在的治疗价值。该项目的中心假设是，神经调节蛋白是一种新型的神经保护剂，可促进缺血性卒中后神经元的存活和功能恢复，并具有延长的治疗窗。为了检验我们的假设，我们将采用以下一组具体目标： (1)研究缺血后NRG-1的剂量依赖性和亚型特异性神经保护作用，（2）确定缺血后NRG-1神经保护作用中涉及的生理学和药理学机制，（3）确定缺血中NRG-1神经保护的治疗窗和长期作用。这项研究将为神经调节蛋白在缺血性脑损伤中的新的和可能的关键作用提供新的见解。这些研究具有巨大的临床潜力，并可能导致缺血性卒中治疗的新的治疗策略。(End摘要）