Molecular Mechanisms of LPS Preconditioning In Stroke

LPS预处理中风的分子机制

• 批准号: 8293099
• 负责人: MARY P STENZEL-POORE
• 金额: $ 35.86万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293099
• 关键词: Acute; Agonist; Appearance; Atherosclerosis; Blood flow; Brain; Brain Injuries; Brain Ischemia; Cardiovascular Surgical Procedures; Carotid Endarterectomy; Cell Survival; Computer Analysis; Computer Simulation; Coronary Arteriosclerosis; Coronary Artery Bypass; Data; Development; Dose; Event; Fingerprint; Gene Expression Profile; Gene Targeting; Genes; Genomics; Grant; Hour; IRF3 gene; Impaired cognition; In Vitro; Individual; Injury; Interferon Type I; Interferons; Ischemia; Ischemic Brain Injury; Lead; Lesion; Ligands; Lipopolysaccharides; Maintenance; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mus; Neurologic; Neuroprotective Agents; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Process; Property; Prophylactic treatment; Regulation; Regulator Genes; Research; Risk; Role; Secondary to; Seminal; Signal Transduction; Small Interfering RNA; Stimulus; Stroke; TLR3 gene; TNF gene; Testing; Therapeutic; Toll-like receptors; Transfection; United States; Vascular Diseases; Work; heart valve replacement; in vivo; insight; mortality; neuroprotection; novel; overexpression; preconditioning; programs; prophylactic; receptor; repaired; response; response to injury; transcription factor

DESCRIPTION (provided by applicant): Brain ischemia is one of the leading causes of morbidity and mortality in the United States, and many cases of ischemia are secondary to cardiovascular surgery. Pretreatment or preconditioning with a Tol-like Receptor agonist, LPS, induces a protective response to ischemic injury referred to as ischemic tolerance. This competitive renewal application seeks to elucidate the molecular events that define ischemic tolerance induced by LPS preconditioning. Our previous research revealed a novel genomic fingerprint that implicates type I interferons (IFNs) as primary effectors of LPS induced tolerance to ischemic injury. We discovered that the IFN transcription factor, IRF3 is required for LPS preconditioning and our recent preliminary work suggests that the IFN transcription factor, IRF7 may also be required. In addition we have found that the IFN genomic fingerprint extends to ischemic protection of the brain induced by two other preconditioning stimuli: a TLR9 ligand, unmethylated CpG ODNs and low dose ischemia thus broadening its importance. The appearance of a novel IFN fingerprint in neuroprotection supports a new working model of preconditioning in which Toll-like receptors are the central feature. Elucidation of the function of the IFN response may provide insight into the mechanism of TLR induced prophylactic treatment for stroke and lead to the development of a new TLR induced pathway of acute neuroprotection that by-passes the need for prior preconditioning. These findings have led us to hypothesize that LPS preconditioning induces neuroprotection through IRF3/IRF7 driven expression of a core set of genes that result in complimentary pathways of neuroprotection. We shall test the precepts of this model and its therapeutic potential in three aims: Aim 1. Elucidate the function of transcription factors IRF3 and IRF7 in TLR-induced neuroprotection. Aim 2. To determine the mechanism by which the IFN fingerprint confers neuroprotection in response to ischemic injury. Aim 3. Test whether direct activation of IRF3/7 in the acute setting of stroke leads to ischemic neuroprotection.

描述（由申请人提供）：脑缺血是美国发病和死亡的主要原因之一，许多缺血病例继发于心血管手术。使用 Tol 样受体激动剂 LPS 进行预处理或预处理可诱导对缺血性损伤的保护性反应，称为缺血耐受。这种竞争性更新应用旨在阐明定义 LPS 预处理诱导的缺血耐受性的分子事件。我们之前的研究揭示了一种新的基因组指纹，表明 I 型干扰素 (IFN) 是 LPS 诱导缺血性损伤耐受的主要效应物。我们发现LPS预处理需要IFN转录因子IRF3，并且我们最近的初步工作表明IFN转录因子IRF7也可能是必需的。此外，我们发现 IFN 基因组指纹延伸到由另外两种预处理刺激诱导的大脑缺血保护：TLR9 配体、未甲基化的 CpG ODN 和低剂量缺血，从而扩大了其重要性。神经保护中新型 IFN 指纹的出现支持了一种新的预处理工作模型，其中 Toll 样受体是核心特征。阐明 IFN 反应的功能可以深入了解 TLR 诱导的中风预防性治疗机制，并导致开发一种新的 TLR 诱导的急性神经保护途径，从而绕过预先预处理的需要。这些发现使我们推测 LPS 预处理通过 IRF3/IRF7 驱动一组核心基因的表达来诱导神经保护，从而产生神经保护的互补途径。我们将在三个目标上测试该模型的原理及其治疗潜力： 目标 1. 阐明转录因子 IRF3 和 IRF7 在 TLR 诱导的神经保护中的功能。目标 2. 确定 IFN 指纹对缺血性损伤产生神经保护作用的机制。目标 3. 测试在中风急性情况下直接激活 IRF3/7 是否会导致缺血性神经保护。