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

TLR4依赖性无菌炎症在介导SAH后不良后果中的作用

• 批准号: 9386587
• 负责人: Khalid A. Hanafy
• 金额: $ 25.95万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386587
• 关键词: Address; Admission activity; Affect; Alpha Cell; American; Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Antigen-Presenting Cells; Apoptotic; Autoimmune Process; Bacteria; Brain; Brain hemorrhage; Cell physiology; Cells; Cerebrum; Clip; Coagulation Process; Cognitive; Data; Disease Marker; Elements; Equilibrium; Erythrocytes; Fever; Flow Cytometry; Hematogenous; Hematoma; Hemoglobin; Impaired cognition; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Innate Immune System; Knock-out; Knockout Mice; Link; Lymphocyte; Measures; Mediating; Mediator of activation protein; Microglia; Mus; Myelogenous; Myeloid Cells; Neutrophil Infiltration; Nimodipine; Outcome; Participant; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Publishing; Resolution; Role; Secondary to; Secure; Severity of illness; Signal Transduction; Signal Transduction Pathway; Sterility; Subarachnoid Hemorrhage; Survivors; TLR4 gene; Testing; Tissues; Transforming Growth Factor alpha; Transforming Growth Factor beta; Virus; Western Blotting; adverse outcome; base; cognitive function; fungus; improved; in vivo; inhibitor/antagonist; macrophage; mortality; mouse model; mouse toll-like receptor 4; neuron apoptosis; neutrophil; novel; novel strategies; receptor; response

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.

摘要/总结： 蛛网膜下腔出血影响着 40,000 名正值壮年的美国人；其中一半人会 12 个月内死亡，三分之一的幸存者认知能力较差。唯一的 我们可以在神经重症监护病房为这些患者提供的治疗方法是用夹子固定动脉瘤 或线圈，并给他们服用一种已有 32 年历史的药物，称为尼莫地平。这些治疗方法都没有 解决红细胞引起的持续存在的脑炎症反应。我们的 初步数据和已发表的数据分别确定了 TLR4 和小胶质细胞的作用。 在本提案中，我们将研究先天性细胞内细胞特异性 TLR4 的功能。 免疫系统。具体来说，我们创建了 2 个新颖的 TLR4 条件敲除 小胶质细胞和骨髓细胞。我们将测量发烧、神经元凋亡、血肿清除、 和这些新型条件敲除小鼠的认知结果，以确定其程度 组织驻留巨噬细胞与中性粒细胞影响这些结果。 此外，我们还将研究缺乏 TLR4 对炎症和炎症的体内影响。 使用蛋白质印迹和 TLR4 依赖性药理学抑制剂研究细胞凋亡途径 炎。据我们所知，TLR4在血肿消退中的作用尚未被证实。 检查，更不用说以细胞特异性的方式，也没有脑炎症和细胞凋亡 这些新颖的条件敲除中的信号转导途径。 根据我们的发现，平衡 TLR4 依赖之间平衡的新策略 可以利用炎症和细胞凋亡抑制。另外，我们的初步数据 表明 TLR4 可能在血肿清除中发挥作用；细胞特异性策略可能是 用于减少血肿负荷并消除红细胞引起的脑损伤 炎症反应。