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神经保护疗法 中风。神经结尾蛋白与正常的脑功能有关，以及神经保护 脑缺血。我们实验室的最新工作表明，一个低剂量（2.5ng/kg） 手术内施用的神经蛋白1（NRG-1）减少了缺血诱导的大鼠局灶性神经元死亡 中风模型约为90％，其治疗窗口至少为5.5小时。 NRG-1给药也导致 在神经功能的显着改善中。神经保护与抑制有关 凋亡，星形胶质细胞增多症和白介素-1 mRNA表达。我们已经通过微阵列演示 分析，NRG-1不仅阻止了白介素-1的表达，而且还会减弱广泛的模式 缺血后促炎和应激基因表达。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 急性缺血性中风后治疗个体。该项目的核心假设是神经调节蛋白是 缺血后促进神经元存活和功能恢复的新型神经保护剂 带有扩展的治疗窗口的中风。为了检验我们的假设，我们将采用以下一组 具体目的： （1）检查NRG-1的剂量依赖性和同工型特异性神经保护作用 缺血，（2）确定涉及的生理和药理机制 缺血后NRG-1的神经保护作用，（3）确定治疗窗口和 NRG-1神经保护性缺血的长期影响。这项研究将为一部小说提供新的见解， 神经结合蛋白在缺血性脑损伤中的关键作用。这些研究中有巨大的临床 潜力，可能导致缺血性中风治疗的新治疗策略。