The role of TLR4-dependent sterile inflammation in mediating adverse outcomes after SAH

摘要/总结： 蛛网膜下腔出血影响了40，000名美国人在他们生命的黄金时期;其中一半将 在12个月内死亡，三分之一的幸存者将有一个糟糕的认知结果。唯一的 我们可以在神经重症监护室为这些患者提供的治疗是用夹子固定动脉瘤 或者线圈，给他们一种32年前的药物尼莫地平。这两种治疗方法 解决了红细胞诱导的持续存在的脑炎症反应。我们 初步的，以及公开的，数据分别建立了TLR 4和小胶质细胞的作用。 在这项计划中，我们将研究细胞特异性TLR 4在先天性巨噬细胞中的功能。 免疫系统具体来说，我们已经在以下细胞中创建了2种新的TLR 4条件性敲除： 小胶质细胞和骨髓细胞。我们将测量发热，神经元凋亡，血肿清除， 和认知结果，以确定 组织中的巨噬细胞与中性粒细胞对这些结果有影响。 此外，我们还将研究缺乏TLR 4对炎症和炎症反应的体内影响。 使用蛋白质印迹和TLR 4依赖性的药理学抑制剂的凋亡途径 炎症据我们所知，TLR 4在血肿消退中的作用尚未被证实。 检查，更不用说在细胞特异性的方式，也没有脑炎症和凋亡 这些新的条件性敲除的信号转导途径。 基于我们的发现，新的策略，以打破TLR 4依赖性之间的平衡， 可以利用炎症和凋亡抑制。此外，我们的初步数据显示， 表明TLR 4可能在血肿清除中起作用;细胞特异性策略可能是 用于减少血肿负荷并消除RBC诱导的脑出血。 炎症反应。

Abstract/Summary: Subarachnoid hemorrhage affects 40,000 Americans in the prime of their lives; half of them will die in 12 months, and one third of the survivors will have a poor cognitive outcome. The only treatments we can offer these patients in the Neuro-ICU are securing the aneurysm with a clip or coils and giving them a 32-year-old drug called nimodipine. Neither of these treatments addresses the red blood cell-induced cerebral inflammatory response which persists. Our preliminary, as well as published, data establish a role for TLR4 and microglia individually. In this proposal we will be investigating the function of cell specific TLR4 within the innate immune system. Specifically, we have created 2 novel conditional knockouts of TLR4 on microglia and myeloid cells. We will measure fever, neuronal apoptosis, hematoma clearance, and cognitive outcome in these novel conditional knockout mice to determine the extent to which the tissue resident macrophage versus neutrophil affects these outcomes. Furthermore, we will also be examining the in vivo effects of lack of TLR4 on inflammatory and apoptotic pathways using western blot and pharmacological inhibitors of TLR4-dependent inflammation. To our knowledge, the role of TLR4 in hematoma resolution has not been examined, let alone in a cell-specific manner, nor have cerebral inflammatory and apoptotic signal transduction pathways in these novel conditional knockouts. Based on our findings, novel strategies to tip the balance between TLR4-dependent inflammation and apoptotic inhibition may be exploited. Additionally, our preliminary data indicates that TLR4 might have a role in hematoma clearance; a cell-specific strategy might be employed to decrease hematoma burden and abrogate the RBC-induced cerebral inflammatory response.