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：

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.

假定的小胶质细胞特异性标记的潜在警告，以评估与年龄相关的脑血管神经炎症。

• 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.

女性的肠道营养不良和与年龄有关的神经疾病。

• 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.