Molecular Mechanisms of LPS Preconditioning In Stroke

描述（由申请人提供）：脑缺血是美国发病率和死亡率的主要原因之一，许多缺血病例继发于心血管手术。用Tol样受体激动剂LPS预处理或预调节诱导对缺血性损伤的保护性反应，称为缺血耐受。这种竞争性的更新申请旨在阐明定义LPS预处理诱导的缺血耐受的分子事件。我们以前的研究揭示了一种新的基因组指纹，暗示I型干扰素（IFN）作为LPS诱导的缺血性损伤耐受的主要效应物。我们发现IFN转录因子IRF 3是LPS预处理所必需的，我们最近的初步工作表明IFN转录因子IRF 7也可能是必需的。此外，我们已经发现IFN基因组指纹延伸到由另外两种预处理刺激诱导的脑缺血保护：TLR 9配体、未甲基化的CpG ODN和低剂量缺血，从而扩大了其重要性。一种新的干扰素指纹在神经保护中的出现支持了一种新的预处理工作模型，其中Toll样受体是中心特征。阐明IFN反应的功能可能提供对TLR诱导的预防性治疗中风的机制的深入了解，并导致一个新的TLR诱导的急性神经保护途径的发展，绕过了预先预处理的需要。这些发现使我们假设LPS预处理通过IRF 3/IRF 7驱动的一组核心基因的表达诱导神经保护，这些基因导致神经保护的互补途径。我们将测试该模型的规则及其在三个目标中的治疗潜力：目标1。阐明转录因子IRF 3和IRF 7在TLR诱导的神经保护中的作用。目标二。确定干扰素指纹在缺血性损伤中发挥神经保护作用的机制。目标3：测试在中风的急性情况下IRF 3/7的直接激活是否导致缺血性神经保护。

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.