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: 7204143
• 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/7204143
• 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; abstracting; 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

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)

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