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

肥大细胞信号在中风后连接大脑和肠道

• 批准号: 10058042
• 负责人: Bhanu Priya Ganesh
• 金额: $ 42.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058042
• 关键词: 16S ribosomal RNA sequencing; Acute; Age; Aging; Animal Model; Animals; Autopsy; Bacterial Translocation; Blood; Bone Marrow; Brain; Brain Injuries; Cell Count; Cell Degranulation; Cell Maturation; Cells; Cerebrovascular Circulation; Chronic; Clinical; Communication; Confocal Microscopy; Containment; Cromoglicic Acid; Data; Elderly; Encephalitis; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Foundations; Functional disorder; Gene Expression Profiling; Gut Mucosa; Histamine; Histamine Receptor; Histamine Release; Histology; Home environment; Hour; Human; IgE; Impairment; In Situ Hybridization; Individual; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Intervention Studies; Intestinal Mucosa; Ischemic Stroke; Label; Lasers; Lead; Left; Liver; Lung; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Mononuclear; Mucositis; Mucous Membrane; Mus; Neurological outcome; Oral; Oral Administration; Organ; Outcome; Pathologic; Peripheral; Play; Process; RNA; Receptor Activation; Recovery; Recovery of Function; Risk Factors; Role; Saline; Sampling; Secondary to; Sepsis; Signal Transduction; Source; Spleen; Stroke; Testing; Therapeutic; Therapeutic Intervention; Thinking; Tissues; Work; aged; behavioral outcome; cell age; cell motility; crosslink; design; dysbiosis; first responder; functional disability; gut-brain axis; improved; improved outcome; inflammatory disease of the intestine; innovation; juvenile animal; mast cell; microbiota; migration; mortality; neuroinflammation; neuron loss; novel therapeutic intervention; post stroke; prevent; receptor; recruit; response; sham surgery; stem cells; stroke model; stroke outcome; stroke patient; stroke recovery; therapeutic target; trafficking

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.

项目摘要/摘要： 中风后炎症（PSI）是中风后损伤和恢复的关键决定因素。 越来越多的证据表明，中风的外周炎症反应具有重要作用 在决定神经系统结果中的作用。许多炎症过程是由 缺血性中风并导致进一步的损害。肥大细胞 (MC) 释放大量 组胺 (HA) 是一种促炎递质，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，肠道是主要的器官之一 HA 的来源尚未探索。 “脑肠轴”响应的重要性 中风越来越受到人们的重视。中风引起中枢和外周血管的恶性循环 通过“肠-脑轴”内的双向通讯产生炎症。维持 肠道屏障功能的完整性对于防止细菌移位和 脓毒症是老年中风患者死亡的主要原因。 组胺释放和肠道 MC (gMC) 激活会导致严重的肠道炎症。我的 构成该提案基础的初步研究结果表明，中风诱发的肠道 HA 受体激活是中风后“脑肠轴”通讯的关键介质。然而， 中风后肠道 HA 信号的时间和信号传导，以及操纵该轴以改善的潜力 功能恢复尚未进行研究。中风会导致血液中组胺含量激增 与年轻小鼠相比，老年小鼠显着且持续升高。我们假设这 继发于肠道肥大细胞的激活。外周血凝素信号传导的抑制 肠道粘膜将导致外周和大脑炎症的抑制，并改善 中风动物模型的功能恢复并降低死亡率。我会测试中央 假设神经炎症是由外周肠道组胺信号传导升高引起的，MC 脱粒、肠道屏障破坏、细菌遏制能力丧失和亲 炎症性肥大细胞进入大脑。这对于老年小鼠来说意义更为深远。年迈的MC是 已知其处于增强的激活状态，组胺水平较高。因此，衰老是一个 影响HA水平的主要因素。鉴于衰老伴随着慢性低水平 炎症并且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。初步数据表明，抑制 中风后外周组胺受体 (HR) 激活并控制 HA 释放 改善结果。该 R21 将研究 MC 和 HR 的分子机制 肠道激活作为中风后更好恢复的潜在治疗靶点。

项目成果

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells.

• DOI: 10.3389/fragi.2021.797562
• 发表时间: 2021
• 期刊: FRONTIERS IN AGING
• 作者: Noh, Brian;Blasco-Conesa, Maria P.;Lai, Yun-Ju;Ganesh, Bhanu Priya;Urayama, Akihiko;Moreno-Gonzalez, Ines;Marrelli, Sean P.;Mccullough, Louise D.;Moruno-Manchon, Jose Felix
• 通讯作者: Moruno-Manchon, Jose Felix

Potential caveats of putative microglia-specific markers for assessment of age-related cerebrovascular neuroinflammation.

• DOI: 10.1186/s12974-020-02019-5
• 发表时间: 2020-12-01
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Honarpisheh P;Lee J;Banerjee A;Blasco-Conesa MP;Honarpisheh P;d'Aigle J;Mamun AA;Ritzel RM;Chauhan A;Ganesh BP;McCullough LD
• 通讯作者: McCullough LD

Gut dysbiosis and age-related neurological diseases in females.

• DOI: 10.1016/j.nbd.2022.105695
• 发表时间: 2022-06-15
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Korf, Janelle M.;Ganesh, Bhanu P.;McCullough, Louise D.
• 通讯作者: McCullough, Louise D.