Toll-like Receptors: Novel targets of neuroprotection in ischemic brain injury

描述（由申请人提供）：炎症是卒中期间脑损伤发病机制的主要组成部分。在炎症级联反应中显著参与的细胞信号传导途径通过Toll样受体（TLR）启动。因此，TLR可能是中风治疗的新靶点。TLR 4负责由脂多糖（LPS）全身施用诱导的缺血耐受。潜在的有害副作用妨碍了翻译。我们已经发现另外的TLR（TLR 7和TLR 9）也是诱导针对中风的预处理的有效靶标。用TLR 9激动剂CpG ODNs预处理，在随后的中风期间重新编程细胞信号传导，并且所得的炎症细胞信号传导被改变为有效的神经保护。CpG ODN在人类中耐受性良好，为高风险患者（例如新发TIA，等待CABG手术）提供快速翻译作为中风前治疗。在这里，我们提出了这种新的预防性中风治疗的特点，并证明了中风的疗效和免疫细胞激活。我们将讨论神经保护的潜在机制，以及这些机制是否作用于全身和/或位于中枢神经系统，因为人类治疗可能最好是全身或中枢。目标1.由TLR 9激动剂CpG ODN诱导的神经保护的表征。目标3。确定LPS预处理的主要诱导物和效应物是否由咪喹莫特和CpG预处理途径共享。目标二。确定CNS驻留细胞和全身造血细胞对TLR 9诱导的神经保护的相对贡献。目标3：确定TNFa和IFNb是否是由TLR 9（CpG）预处理引起的缺血耐受的关键效应物。目标4。确定CpG预处理是否通过调节TLR信号通路重新编程对卒中的反应。公共卫生相关性：保护大脑免受未来中风。在这里，我们描述了一种治疗方法，通过这种方法，我们可以改变大脑中的化学事件，以便在中风发生时产生保护作用。通过这种治疗，由导致严重脑损伤的中风引起的大脑中的破坏性多米诺骨牌效应可以重新定向到神经保护级联反应。这里的研究将测试这种治疗是否可以发展成为中风高危患者的潜在治疗方法。

DESCRIPTION (provided by applicant): Inflammation is a major component in the pathogenesis of brain injury during stroke. Cell signaling pathways prominently involved in the inflammatory cascade are initiated through Toll-like receptors (TLRs). Thus TLRs may be novel targets for stroke therapeutics. TLR4 is responsible for ischemic tolerance induced by systemic administration of lipopolysaccharide (LPS). Potential deleterious side effects preclude translation. We have found that additional TLRs (TLR7 & TLR9) are also potent targets to induce preconditioning against stroke. Pretreatment with the TLR9 agonist, CpG ODNs, reprograms cell signaling during subsequent stroke and the resultant inflammatory cell signaling is changed to potent neuroprotection. CpG ODNs are well tolerated in humans offering rapid translation as pre-stroke treatment for patients at high risk (e.g. new TIA, pending CABG surgery). Here we propose to characterize this novel prophylactic stroke therapy and demonstrate the efficacy and immune cell activation in the setting of stroke. We will address the potential mechanisms that underlie neuroprotection and whether these mechanisms act systemically and/or are located in the CNS as human treatments may optimally be directed systemically or centrally. Aim 1. Characterization of neuroprotection induced by the TLR9 agonist, CpG ODNs. Aim 3. Determine whether the primary inducers and effectors of LPS preconditioning are shared by imiquimod and CpG preconditioning pathways. Aim 2. Determine the relative contribution of CNS resident cells and systemic hematopoietic cells to TLR9 induced neuroprotection. Aim 3. Determine whether TNFa and IFNb are critical effectors of ischemic tolerance elicited by TLR9 (CpG) preconditioning. Aim 4. Determine whether CpG preconditioning reprograms the response to stroke through modulation of TLR signaling pathways. PUBLIC HEALTH RELEVANCE: Protecting the brain against future stroke. Here we describe a treatment by which we can modify chemical events in brain so that protection will result if a stroke were to occur. With this treatment, the damaging domino effect in brain, caused by the stroke that leads to profound brain injury, can be redirected towards a neuroprotective cascade. Studies here will test whether such treatment can be developed into a potential treatment for patients at high risk of stroke.