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.

项目摘要 这项拟议的研究将研究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，大多数人都会烧伤 患者不会死于原发损伤，而是死于并发症，如败血症。此外，老化烧伤 患者经常经历更大的神经损伤，这可能源于高度紧张 神经炎。临床和实验证据表明，健康老年人处于一种 基础炎症状态，称为“发炎”，可导致组织损伤和 修理。我们和其他人认为，发炎是由细菌产品移位引起的 肠腔和接触这些产品会触发促炎细胞因子的产生，并 趋化因子，包括肿瘤坏死因子、白介素1β、白介素6和C-C基序趋化因子 配体2(CCL2)。在我们临床相关的烫伤小鼠模型中，新的初步数据证实 遭受烧伤的老年小鼠循环中危险相关分子水平升高 模式(潮湿)，以及与增加相一致的肠上皮屏障完整性的更大破坏 神经炎症的标记物。老年人群中的神经炎症和烧伤都已经 与血脑屏障的破坏、精神错乱和其他认知能力下降的迹象有关。从这些 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。为了验证这一假设，在目标1中，我们将 通过鉴定幼年和老年假手术和烧伤小鼠肠道渗漏的机制 肠上皮细胞凋亡/坏死性下垂、肠上皮细胞增殖和肠干细胞标志物 在体内和体外利用整个组织、分离的上皮和肠道器官类物质，以及测量 血源性肠源性细菌和细菌细胞壁成分。在目标2中，我们将检查血脑 多项屏障测量对青年和老年假手术及烧伤小鼠屏障完整性的影响 渗透性。此外，我们将检测促炎细胞因子和趋化因子以及小胶质细胞的水平。 以及脑区内星形胶质细胞的激活。最后，我们将确定限制肠屏障损害是否在 烧伤会减少大脑中的神经炎性标志物。这些研究将扩大我们对 在烧伤的背景下，高龄是如何改变肠道的，以及肠道通透性对 神经炎。我们希望我们的工作将导致新疗法的开发，以治疗 各年龄段烧伤患者的过度炎症反应及其后果。