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

描述(由申请人提供)：炎症是中风期间脑损伤发病机制的主要组成部分。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，TLRs可能成为中风治疗的新靶点。TLR4参与全身注射脂多糖(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，更多的TLRs(TLR7和TLR9)也是诱导卒中预适应的有效靶点。用TLR9激动剂CpG ODns预处理后，在随后的卒中中，细胞信号重新编程，由此产生的炎症细胞信号改变为有效的神经保护。CpG ODN在人类中耐受性良好，为高危患者(例如，新的TIA，等待CABG手术)提供快速转换为卒中前治疗。在这里，我们建议对这种新的预防性卒中疗法进行描述，并展示其在卒中环境中的有效性和免疫细胞激活。我们将讨论神经保护的潜在机制，以及这些机制是否系统地起作用和/或位于中枢神经系统，因为人类治疗可能以系统或中枢为最佳指导。目的1.TLR9激动剂CpG ODns诱导的神经保护作用的特征。目的3.确定咪喹莫特和CpG两条预适应通路是否共有内毒素预适应的主要诱导物和效应分子。目的2.确定中枢神经系统驻留细胞和系统造血细胞在TLR9诱导的神经保护中的相对作用。目的3.确定TLR9(CpG)预适应诱导的缺血耐受的关键效应因子是否为肿瘤坏死因子α(TNFa)和干扰素B(IFNb)。目的4.确定CpG预适应是否通过调节TLR信号通路重新编程对卒中的反应。与公共健康相关：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，以便在发生中风时起到保护作用。通过这种治疗，由导致严重脑损伤的中风在大脑中造成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.