Gut-brain axis at the intersection of aging and traumatic injury

衰老与外伤交叉点的肠脑轴

• 批准号: 10679217
• 负责人: Travis Michael Walrath
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10679217
• 关键词: Abbreviations; Age; Aging; Alkaline Phosphatase; Analysis of Variance; Apoptosis; Astrocytes; Bacteria; Bacterial Translocation; Biology; Blood; Blood - brain barrier anatomy; Blood brain barrier dysfunction; Body Surface Area; Brain; Brain region; Burn injury; CCL2 gene; CCR; CREB1 gene; CXCL2 gene; Calcium Binding; Cell Death; Cell Proliferation; Cell Wall; Circulation; Clinical; Clinical Research; Colony-forming units; Cyclic AMP-Responsive DNA-Binding Protein; Data; Delirium; Development; Distant; Elderly; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Exhibits; Exposure to; Fluorescein; Fluorescein-5-isothiocyanate; Functional disorder; G-Protein-Coupled Receptors; Glial Fibrillary Acidic Protein; Goals; Hematoxylin and Eosin Staining Method; Hippocampus; Immunofluorescence Immunologic; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Incidence; Inflammaging; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Integral Membrane Protein; Interleukin-1 beta; Interleukin-6; Interleukins; Intestinal permeability; Intestines; Ischemic Bowel Disease; Isothiocyanates; Knock-out; Knockout Mice; LGR5 gene; Lead; Leaky Gut; Leucine-Rich Repeat; Ligands; Lipopolysaccharides; MAP Kinase Gene; Measures; Mediating; Microglia; Mitogen-Activated Protein Kinases; Molecular; Mucous Membrane; Mus; Myosin Light Chain Kinase; Myosin Light Chains; Neurocognitive; Neurologic; OLFM4 gene; Organ; Organoids; Outcome; Patients; Pattern; Permeability; Phosphorylation; Play; Production; Proliferating; Proteins; Psyche structure; Publishing; Risk Factors; Role; Sepsis; Skin; Small Intestines; TNF gene; Testing; Tight Junctions; Time; Tissues; Trauma; Traumatic injury; Wild Type Mouse; Work; age effect; age related; aged; aging population; blood-brain barrier permeabilization; body system; chemokine; chemokine receptor; clinically relevant; commensal bacteria; cytokine; cytokine release syndrome; dentate gyrus; experience; experimental study; gastrointestinal epithelium; gut bacteria; gut-brain axis; ileum; in vivo; inflammatory marker; injured; intestinal barrier; intestinal epithelium; intestinal fatty acid binding protein; intraperitoneal; ionization; mRNA Expression; mental state; mesenteric lymph node; mortality; mouse model; neuroinflammation; novel; novel strategies; novel therapeutics; occludin; severe burns; stem; stem cell biomarkers; stem cells; stemness; systemic inflammatory response; tissue injury; tissue repair; transcription factor

Project Summary The proposed studies will examine mechanisms by which advanced age increases intestinal permeability and neuroinflammation after burn injury using a clinically relevant mouse model. Regardless of age, most burn patients do not die from primary injuries, but rather from complications, such as sepsis. Further, aged burn patients often experience greater neurological impairments, which may stem from heightened neuroinflammation. Clinical and experimental evidence reveal that healthy aged subjects are in an elevated basal inflammatory state, referred to as “inflammaging,” which can contribute to deficits in tissue injury and repair. We and others believe that inflammaging is caused by translocation of bacterial products from the intestinal lumen and that exposure to these products triggers the production of pro-inflammatory cytokines and chemokines, including tumor necrosis factor alpha (TNF), interleukin (IL)-1β, IL-6, and C-C Motif Chemokine Ligand 2 (CCL2). Novel preliminary data in our clinically-relevant murine model of scald burn injury confirm that aged mice who sustain a burn injury have heightened circulating levels of danger-associated molecular patterns (DAMPs), and a greater breach in intestinal epithelial barrier integrity that coincides with an increase in markers of neuroinflammation. Both neuroinflammation and burn injury in the aged population have been correlated with breaches in the blood brain barrier, delirium, and other signs of cognitive decline. From these observations, we hypothesize that post-burn gut leakiness seen in aged mice is driven by excessive IEC death, ISC dysfunction, and reduced IEC proliferation. Additionally, these changes in the gut lead to leakiness of the blood brain barrier and neuroinflammation. To test this hypothesis, in Aim 1, we will investigate the mechanisms behind gut leakiness in young and aged sham and burn-injured mice by identifying intestinal epithelial cell apoptosis/necroptosis, epithelial cell proliferation, and intestinal stem cell markers in vivo and in vitro utilizing whole tissue, isolated epithelium, and intestinal organoids, along with measuring blood-borne gut-derived bacteria and bacterial cell wall components. In Aim 2, we will examine blood brain barrier integrity in young and aged sham and burn-injured mice using multiple measures of barrier permeability. Further, we will examine the levels of pro-inflammatory cytokines and chemokines, and microglial and astrocyte activation within brain regions. Finally, we will determine if limiting intestinal barrier damage after burn injury reduces neuroinflammatory markers in the brain. These studies will expand our understanding of how advanced age alters the gut in the context of burn injury and the impact of intestinal permeability on neuroinflammation. It is our hope that our work will lead to the development of novel therapies to treat the excessive inflammatory response and consequences of that inflammation in burn patients of all ages.

项目概要 拟议的研究将探讨高龄增加肠道通透性和 使用临床相关的小鼠模型研究烧伤后的神经炎症。无论年龄大小，大多数烧伤 患者并非死于原发性损伤，而是死于脓毒症等并发症。此外，老化烧伤 患者通常会经历更严重的神经功能障碍，这可能是由于 神经炎症。临床和实验证据表明，健康的老年受试者处于升高的状态 基础炎症状态，称为“炎症”，可能导致组织损伤和损伤 维修。我们和其他人认为，炎症是由细菌产物从 肠腔，接触这些产品会触发促炎细胞因子的产生 趋化因子，包括肿瘤坏死因子 α (TNFα)、白细胞介素 (IL)-1β、IL-6 和 C-C 基序趋化因子 配体 2 (CCL2)。我们临床相关的烫伤小鼠模型的新初步数据证实 遭受烧伤的老年小鼠的危险相关分子的循环水平升高 模式（DAMP），以及肠上皮屏障完整性的更大破坏，这与增加 神经炎症标志物。老年人群中的神经炎症和烧伤都已被 与血脑屏障的破坏、谵妄和其他认知能力下降的迹象相关。从这些 根据观察，我们假设老年小鼠烧伤后肠道渗漏是由过量的 IEC 引起的 死亡、ISC 功能障碍和 IEC 增殖减少。此外，肠道的这些变化会导致 血脑屏障渗漏和神经炎症。为了检验这个假设，在目标 1 中，我们将 通过识别来研究年轻和老年假小鼠和烧伤小鼠肠道渗漏背后的机制 肠上皮细胞凋亡/坏死性凋亡、上皮细胞增殖和肠干细胞标记物 体内和体外利用整个组织、分离的上皮和肠类器官，并测量 血源性肠道来源的细菌和细菌细胞壁成分。在目标 2 中，我们将检查血脑 使用多种屏障措施测量年轻和老年假小鼠和烧伤小鼠的屏障完整性 渗透性。此外，我们将检查促炎细胞因子和趋化因子以及小胶质细胞的水平 以及大脑区域内星形胶质细胞的激活。最后，我们将确定是否限制肠道屏障损伤 烧伤会降低大脑中的神经炎症标志物。这些研究将扩大我们对 高龄如何在烧伤的情况下改变肠道以及肠道通透性对肠道的影响 神经炎症。我们希望我们的工作能够开发出新的疗法来治疗 所有年龄段烧伤患者的过度炎症反应和炎症后果。