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: 7369799
• 负责人: BYRON D. FORD
• 金额: $ 18.82万
• 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/7369799
• 关键词: Acute; Animals; Attenuated; Behavior; Blood Pressure; Brain; Cause of Death; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cessation of life; Clinical; Clinical Trials; Dose; Gene Expression; Goals; Heart Rate; Histology; Hour; Human; Individual; Infarction; Inflammation; Inflammatory; Inhibition of Apoptosis; Injection of therapeutic agent; Interleukin-1; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Kinetics; Lead; Long-Term Effects; Measures; Microarray Analysis; Modeling; Nervous System Physiology; Neuregulin 1; Neuregulins; Neurologic; Neurons; Neuroprotective Agents; Pattern; Pharmaceutical Preparations; Physiological; Play; Protein Isoforms; Rattus; Recovery of Function; Research Personnel; Role; Safety; Score; Standards of Weights and Measures; Stress; Stroke; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Toxic effect; United States; Week; Work; astrogliosis; brain cell; disability; improved; insight; mRNA Expression; macrophage; neuron loss; neuronal survival; neuroprotection; novel; novel strategies; novel therapeutics; pre-clinical; programs; stroke therapy; therapy development

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 (2.5ng/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.

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神经保护疗法， 中风神经调节蛋白与正常的脑功能有关，也与以下神经保护作用有关： 脑缺血我们实验室最近的工作表明，单次低剂量（2.5ng/kg）的 动脉内给予神经调节蛋白-1（NRG-1）减少大鼠局灶性脑缺血诱导的神经元死亡 中风模型的治疗时间窗至少为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 凋亡、星形胶质细胞增生和白细胞介素-1 mRNA表达。我们已经通过微阵列证明了 分析表明，NRG-1不仅阻断了白细胞介素-1的表达，而且还减弱了广泛的模式， 缺血后促炎和应激基因的表达。我们进一步表明，NRG-1直接 使用培养的巨噬细胞阻断促炎基因表达。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，神经调节蛋白代表了一种新的、有效的神经保护策略，其在以下方面具有潜在的治疗价值： 治疗急性缺血性中风后的个体。该项目的中心假设是，神经调节蛋白是 促进缺血后神经元存活和功能恢复的新型神经保护剂 治疗窗延长的中风。为了验证我们的假设，我们将使用以下一组 具体目标： (1)为了检查NRG-1的剂量依赖性和亚型特异性神经保护作用， 缺血，（2）为了确定参与缺血的生理和药理学机制， 缺血后NRG-1的神经保护作用和（3）确定治疗窗， NRG-1在缺血中神经保护的长期作用。这项研究将为一部小说提供新的视角， 神经调节蛋白在缺血性脑损伤中可能起关键作用。本文中的这些研究具有巨大的临床意义。 这可能为缺血性卒中的治疗带来新的治疗策略。