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Cerebral ischemia and expression of stress genes

脑缺血与应激基因的表达

基本信息

批准号：
7197449
负责人：
FRANK A WELSH
金额：
$ 34.14万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-05-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7197449
关键词：
Animals Attenuated Brain Brain-Derived Neurotrophic Factor Cells Cerebral Ischemia Cerebrum Ciliary Neurotrophic Factor Condition Cytokine Inducible SH2-Containing Protein Cytokine Signaling Dexamethasone Feedback Genes Human Immune system In Situ Hybridization Infarction Inflammation Inflammatory Inflammatory Response Ischemia Ischemic Brain Injury Lesion Ligands Measures Mediating Methods Middle Cerebral Artery Occlusion Nerve Growth Factor 1 Nerve Growth Factor Pathway Pathway interactions Peptides Rattus Receptor Signaling Signal Transduction Small Interfering RNA Spreading Cortical Depression Stimulus Stress Stroke TIS11 protein TLR4 gene TLR7 gene Testing Toll-like receptors Up-Regulation Viral Proteins Western Blotting attenuation cytokine design immunocytochemistry inhibitor/antagonist innovation neuroprotection neurotrophic factor novel strategies novel therapeutics preconditioning protective effect therapeutic target vector

项目摘要

DESCRIPTION (provided by applicant): Current therapies for human stroke have limited efficacy. Recent studies indicate that there are protective mechanisms residing within the brain that can be activated using preconditioning stimuli. Identification of these mechanisms may provide new therapeutic targets for stroke in humans. The central hypothesis of this proposal is that preconditioning upregulates inhibitors of inflammation that protect the brain against ischemia. Enhancing the expression of inflammatory inhibitors after stroke is a novel strategy to attenuate ischemic damage. The central hypothesis will be tested in four specific aims. First, the timecourse of and regional expression of selected inhibitors of inflammation will be measured after preconditioning. Second, the causative relationship between these inhibitors and neuroprotection will be assessed by determining whether attenuation of their expression abrogates the induction of tolerance to ischemia. Third, we will determine whether agents that specifically activate Toll-like receptors upregulate inhibitors of inflammation and induce tolerance to ischemia. Finally, we will determine whether neurotrophic factors, known to be upregulated by preconditioning, themselves increase the expression of inhibitors of inflammation and whether antagonism of this expression attenuates the protective effects of the neurotrophins against ischemia. These studies will test whether upregulation of inhibitors of inflammation is a major mechanism contributing to ischemic tolerance. Enhancement of endogenous pathways that suppress inflammation is an innovative and promising strategy for the treatment of stroke in humans.

描述（由申请人提供）：目前治疗人类中风的方法疗效有限。最近的研究表明，大脑中存在保护机制，可以通过预处理刺激激活。这些机制的确定可能为人类中风提供新的治疗靶点。这一提议的中心假设是，预处理上调炎症抑制剂，保护大脑免受缺血。增强脑卒中后炎症抑制剂的表达是一种减轻缺血性损伤的新策略。中心假设将在四个具体目标中得到检验。首先，在预处理后测量选定的炎症抑制剂的时间进程和区域表达。其次，这些抑制剂与神经保护之间的因果关系将通过确定其表达的衰减是否会消除对缺血耐受的诱导来评估。第三，我们将确定特异性激活toll样受体的药物是否上调炎症抑制剂并诱导对缺血的耐受。最后，我们将确定神经营养因子（已知通过预处理而上调）本身是否会增加炎症抑制剂的表达，以及这种表达的拮抗是否会减弱神经营养因子对缺血的保护作用。这些研究将测试炎症抑制剂的上调是否是促进缺血耐受的主要机制。增强抑制炎症的内源性途径是治疗人类中风的一种创新和有前途的策略。