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Interleukin-1 alpha as a novel treatment for ischemic stroke

Interleukin-1 alpha 作为缺血性中风的新型治疗方法

基本信息

批准号：
10418778
负责人：
Gregory Jaye Bix
金额：
$ 28.54万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418778
关键词：
Acute Acute Brain Injuries Animals Biochemical Biochemical Genetics Blood Platelets Blood Vessels Brain Brain imaging Cause of Death Cells Cerebral Ischemia Chronic Clinical Trials Cre-LoxP Dose Encephalitis Endothelial Cells Endothelium Enterobacteria phage P1 Cre recombinase Exposure to Extracellular Matrix Gender Generations Genetic Techniques Glucose Goals Impairment In Vitro Infarction Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 Receptors Interleukin-1 alpha Ischemic Penumbra Ischemic Stroke Knockout Mice LoxP-flanked allele Microglia Middle Cerebral Artery Occlusion Mus Neuronal Injury Neurons Neuroprotective Agents Outcome Assessment Oxidative Stress Oxygen Pathway interactions Phase Physiologic pulse Play Process Protein Isoforms Publishing Recovery of Function Reperfusion Therapy Role Signal Transduction Source Stroke Techniques Therapeutic Up-Regulation Vital Statistics age effect angiogenesis base brain magnetic resonance imaging cytokine deprivation disability effective therapy excitotoxicity functional outcomes hemodynamics in vivo inhibitor injury and repair male neuroprotection neurorestoration novel perlecan post stroke post-stroke angiogenesis repaired side effect spatiotemporal stroke model stroke recovery stroke therapy therapeutic target young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Stroke is a major cause of death and disability worldwide and more effective therapies are urgently needed. Unfortunately, all clinical trials that have targeted the primary mechanisms of neuronal injury caused by cerebral ischemia (CI) (i.e. oxidative stress and excitotoxicity) have failed. CI also induces a potent local inflammatory response that leads to progressive damage in the ischemic penumbra. However, emerging evidence suggest that inflammation may also initiate key post-stroke repair processes including angiogenesis leading to long-term functional recovery. For these reasons we propose that inflammation is an attractive therapeutic target for stroke recovery. In support of this, we have recently shown that endogenous post-stroke brain upregulation of the proinflammatory cytokine interleukin-1 (IL-1) isoform IL-1 is tightly regulated in a cell-specific fashion (microglia acutely and platelets chronically) suggesting that it could play important roles in both injury and repair, respectively. Furthermore, we now demonstrate that delayed (3 day) post-stroke administration of IL-1 promoted post-stroke angiogenesis in mice. This may occur, at least in part, as the result of IL-1-induced generation of the proangiogenic extracellular matrix fragment perlecan LG3. Furthermore, as LG3 has known neuroprotective actions, we hypothesize that IL-1 could be both neuroprotective and neurorestorative in ischemic stroke. In support of this hypothesis, preliminary results suggest that IL-1 administered systemically (IV) or intra-arterially (IA) immediately after reperfusion in mice subjected to transient middle cerebral artery occlusion is well tolerated, profoundly neuroprotective and functionally restorative. Therefore, we hypothesize that IL-1 may represent a novel neuroprotective agent for ischemic stroke. To investigate the neuroprotective potential and mechanism(s) of action of IL-1 in experimental ischemic stroke, we propose the following aims: Aim 1: Determine the role of acute and chronic endogenous IL-1 in ischemic stroke. Aim 2: Determine the therapeutic potential of IL-1 in experimental ischemic stroke. Aim 3: Determine the neuroprotective mechanism(s) of IL-1 action. Successful completion of these studies will increase our understanding of the role of endogenous IL-1 at different stages after stroke, determine its therapeutic potential and mechanism(s) of action, and support IL-1 as a promising novel stroke therapy.

项目总结/文摘