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

描述（由申请人提供）：炎症是脑卒中时脑损伤发病机制的重要组成部分。参与炎症级联反应的细胞信号通路是通过toll样受体（TLRs）启动的。因此，tlr可能是脑卒中治疗的新靶点。TLR4负责全身脂多糖（LPS）诱导的缺血耐受。潜在的有害副作用阻碍了翻译。我们发现额外的tlr （TLR7和TLR9）也是诱导卒中预处理的有效靶点。用TLR9激动剂CpG ODNs预处理，在随后的中风中重新编程细胞信号，由此产生的炎症细胞信号转变为有效的神经保护。CpG ODNs在人类中具有良好的耐受性，可快速转化为高风险患者（例如新TIA，等待CABG手术）的脑卒中前治疗。在这里，我们提出表征这种新的预防性中风治疗，并证明在卒中设置的疗效和免疫细胞活化。我们将探讨神经保护背后的潜在机制，以及这些机制是否系统性和/或位于中枢神经系统，因为人类治疗可能是系统性或集中性的最佳指导。目的1。TLR9激动剂cpgodns诱导的神经保护作用的表征。目标3。确定咪喹莫特和CpG预处理途径是否共享LPS预处理的主要诱导剂和效应器。目标2。确定中枢神经系统驻留细胞和全身造血细胞对TLR9诱导的神经保护的相对贡献。目标3。确定TNFa和IFNb是否是TLR9 （CpG）预处理引发的缺血耐受的关键效应因子。目标4。确定CpG预处理是否通过调节TLR信号通路重编程脑卒中反应。公共卫生相关性：保护大脑免受未来中风的影响。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，中风导致的严重脑损伤造成的破坏性多米诺骨牌效应，可以被重新导向神经保护级联反应。这里的研究将测试这种治疗是否可以发展成一种潜在的治疗中风高风险患者的方法。

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.