Mast Cell Signaling Connects the Brain and the Gut Post-Stroke

项目总结/摘要： 卒中后炎症（PSI）是卒中后损伤和恢复的关键决定因素。 越来越多的证据表明，外周炎症反应对中风有重要的影响。 决定神经学结果的作用。许多炎症过程被激活， 缺血性中风并导致进一步损害。肥大细胞（MC）释放大量的 组胺（HA），一种促炎性递质，可增强炎症并有助于 神经元死亡中风后外周器官（如肠道）中的HA信号传导， HA的来源尚未探索。“脑-肠轴”在反应中的重要性 对中风的认识越来越多。脑卒中导致中枢和外周神经系统恶性循环 炎症通过“肠-脑轴”内的双向通信。维持 肠屏障功能的完整性对于防止细菌移位是极其重要的， 败血症是老年中风患者死亡的主要原因。 组胺释放和肠道MC（gMC）活化导致严重的肠道炎症。我 初步的发现，这是这个建议的基础，暗示中风引起的肠道 HA受体激活是卒中后“脑-肠轴”通讯的关键介质。然而，在这方面， 中风后肠道HA信号传导的时间和潜力，以及操纵这一轴以改善 尚未研究功能恢复。中风会导致血液中的组胺浓度升高， 在老年小鼠和年轻小鼠中显著且持续升高。我们假设这 继发于肠道肥大细胞的激活。外周血中HA信号传导的抑制 肠粘膜将导致外周和脑炎症的抑制，并改善 功能恢复和降低中风动物模型的死亡率。我会测试中央 假设神经炎症是由外周肠组胺信号传导升高引起的， 脱颗粒，肠道屏障破坏，细菌遏制损失和前- 炎性肥大细胞转移到大脑这在老年小鼠中将更加深刻。老年MC 已知随着组胺水平的升高，处于激活增强状态。因此，衰老是一种 影响HA水平的主要因素。鉴于衰老伴随着慢性低水平的 炎症，是中风的不可改变的危险因素，我将使用老年（Ag）小鼠来研究 gMC介导的组胺信号在PSI中的作用。初步数据显示， 卒中后外周组胺受体（HR）激活和HA释放控制 改善结果。本R21将研究MC和HR的分子机制 肠内激活作为中风后更好恢复的潜在治疗靶点。

PROJECT SUMMARY / ABSTRACT: Post-stroke inflammation (PSI) is a critical determinant of damage and recovery after stroke. Increasing evidence suggests that peripheral inflammatory responses to stroke have an important role in determining neurological outcome. Many inflammatory processes are activated by ischemic stroke and lead to further damage. Mast cells (MCs) release large quantities of histamine (HA), a pro-inflammatory transmitter that enhances inflammation and contributes to neuronal death. HA-signaling after stroke in peripheral organs such as the gut, one of the major sources of HA, have not been explored. The importance of the "BRAIN-GUT AXIS" in response to stroke is increasingly recognized. Stroke elicits a vicious cycle of central and peripheral inflammation through bi-directional communication within the "gut-brain axis". Maintaining the integrity of gut barrier function is of utmost importance to prevent bacterial translocation and sepsis, a leading cause of mortality in elderly stroke patients. Histamine release and gut MCs (gMC) activation leads to severe gut inflammation. My preliminary findings, which forms the foundation of this proposal, implicates stroke-induced gut HA receptor activation as a key mediator of "brain-gut axis" communication after stroke. However, the timing and of gut HA-signaling after stroke, and the potential to manipulate this axis to improve functional recovery has not been investigated. Stroke induced a histamine spike in the blood that was significantly and persistently elevated in aged versus young mice. We hypothesize that this is secondary to activation of mast cells in the gut. Inhibition of HA-signaling in the peripheral gut mucosa will lead to a suppression of both peripheral and brain inflammation, and improve functional recovery and reduce mortality in an animal model of stroke. I will test the central hypothesis that neuroinflammation results from elevated peripheral gut histamine signaling, MC degranulation, gut barrier breakdown, loss of bacterial containment and trafficking of pro- inflammatory mast cells to the brain. This will be more profound in aged mice. Aged MCs are known to be in an increased state of activation with higher levels of histamine. Thus, aging is a primary factor influencing the levels of HA. Given that aging is accompanied by chronic low-level inflammation and is a non-modifiable risk factor for stroke, I will use aged (Ag) mice to study the role of gMC-mediated histamine signaling in PSI. Preliminary data suggests that suppressing histamine receptor (HR) activation and controlling HA release in the periphery post-stroke improves outcomes. This R21 will investigate the molecular mechanisms underlying MC and HR activation in the gut as a potential therapeutic target for better recovery after stroke.