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）：当前的人类中风疗法的功效有限。最近的研究表明，大脑中存在保护性机制，可以使用预处理刺激来激活。这些机制的识别可能为人类中风提供新的治疗靶标。该提议的中心假设是，预处理炎症的抑制剂可保护大脑免受缺血的侵害。中风后增强炎症抑制剂的表达是减轻缺血损伤的一种新型策略。中心假设将以四个特定目的进行检验。首先，在预处理后将测量选定的炎症抑制剂的时间和区域表达。其次，这些抑制剂与神经保护之间的致病关系将通过确定其表达衰减是否消除了对缺血的耐受性的诱导。第三，我们将确定专门激活类似收费受体的药物是否会上调炎症的抑制剂并诱导对缺血的耐受性。最后，我们将确定神经营养因子（已知通过预处理而上调）是否会增加炎症抑制剂的表达，以及这种表达的拮抗作用是否会减轻神经营养蛋白对缺血的保护作用。这些研究将测试炎症抑制剂的上调是否是导致缺血性耐受性的主要机制。抑制炎症的内源性途径的增强是人类中风治疗的一种创新且有希望的策略。