Novel Neuroprotective Roles for Neuregulins in the Trea*

Trea* 中神经调节蛋白的新神经保护作用

基本信息

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
项目类别：
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

项目摘要

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，在开发缺血性中风治疗方法方面进展甚微。因此，该项目的总体目标是开发并表征一种新型神经保护疗法中风。神经调节蛋白与正常的大脑功能以及神经保护有关脑缺血。我们实验室最近的工作表明，单次低剂量（2.5ng/kg）动脉内注射神经调节蛋白-1 (NRG-1) 可减少大鼠局灶性缺血诱导的神经元死亡中风模型约 90%，治疗窗口至少 5.5 小时。 NRG-1 给药也导致神经功能的显着改善。神经保护作用与抑制有关细胞凋亡、星形胶质细胞增生和白细胞介素 1 mRNA 表达的影响。我们已经通过微阵列证明分析表明，NRG-1 不仅阻断了 IL-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表达的影响。我们进一步证明 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的神经保护和炎症方面发挥着重要作用。因此，神经调节蛋白代表了一种新颖、有效的神经保护策略，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具有延长治疗窗的中风。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 NRG-1 的剂量依赖性和亚型特异性神经保护作用缺血，（2）确定参与缺血的生理和药理机制 NRG-1 在缺血后的神经保护作用，以及 (3) 确定治疗窗和 NRG-1 对缺血神经保护的长期作用。这项研究将为一部小说提供新的见解也许神经调节蛋白在缺血性脑损伤中发挥着关键作用。这些研究具有巨大的临床意义潜力并可能导致治疗缺血性中风的新治疗策略。