Traumatic Brain Injury and Vascular Disease

创伤性脑损伤和血管疾病

• 批准号: 10553149
• 负责人: Daniel T Eitzman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553149
• 关键词: Acceleration; Adhesives; Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; American; Apolipoprotein E; Arrhythmia; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Markers; Blood Vessels; Bone Marrow; Bone Marrow Cells; Brain Injuries; Cardiac; Cardiomyopathies; Cardiovascular system; Catecholamines; Chronic; Clinical Research; Consensus Development; Control Groups; Cytokine Receptors; Data; Development; Disease; Electrocardiogram; Electron Beam Tomography; Endothelium; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Flow Cytometry; Goals; Histologic; Hyperactivity; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 Receptors; Leukocytes; Ligands; Link; Liquid Chromatography; Magnetic Resonance Imaging; Measures; Mediating; Mediator; Methods; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; Neurocognitive Deficit; P-selectin ligand protein; Pathway interactions; Persons; Preventive therapy; Process; Reactive Oxygen Species; Receptor Inhibition; Receptor Signaling; Recording of previous events; Rehabilitation therapy; Relative Risks; Research; Risk; Role; Severities; Signal Transduction; Stress; Testing; Therapeutic Intervention; Time; Traumatic Brain Injury; United States; United States National Institutes of Health; Vascular Diseases; Veterans; arterial stiffness; atherogenesis; cardiovascular effects; cardiovascular risk factor; coronary artery calcification; cytokine; design; disability; endothelial dysfunction; extracellular; in vitro Assay; in vivo; military veteran; mortality; mortality risk; mouse model; neutrophil; novel strategies; prevent; specific biomarkers; tandem mass spectrometry; therapeutic target; therapy design

Objective: Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the veteran population. In the United States, there are an estimated 5.3 million people living with a TBI-related disability. TBI commonly leads to neurocognitive deficits, however, other systemic effects have also been associated with TBI. Cardiovascular effects include stress-related cardiomyopathy, arrhythmias, ECG repolarization changes, and increased cardiac reactive oxygen species. These effects may be mediated by catecholamine surges, although the mechanism(s) are unclear. In a clinical study of TBI in US veterans, TBI was strongly associated with the severity of coronary artery calcification as measured by electron beam computed tomography, suggesting TBI may promote processes involved in atherogenesis. Importantly, there was a marked independent association of TBI with cardiovascular mortality with a relative risk of 2.89 compared to a non-TBI control group, even after adjusting for typical cardiovascular risk factors. These observations indicate there may be a chronic and potent effect of TBI on atherosclerosis. However, whether these findings represent a direct link between TBI and systemic vascular changes or represent other confounding factors is unclear. The goal of this application is to determine the impact of TBI on vascular disease and to uncover underlying mechanisms responsible for these effects. Based on these results, therapeutic interventions will be tested in attempts to block the vasculopathic effects of TBI. Research Plan: To assess the effect of TBI in vascular disease processes, mouse models of TBI will be used to determine the effects of brain injury on sympathetic activity, vascular function, leukocyte-endothelial interactions and the development of atherosclerosis. Biomarkers and possible mediators will be measured through a combination of flow cytometry, liquid chromatography with tandem mass spectrometry, ELISA’s, magnetic resonance imaging, and histological analyses. Therapies designed to block activation of candidate adrenergic and downstream cytokine-triggered inflammatory pathways following TBI will be tested using relevant vascular endpoints. Methods: The strategy to accomplish the objectives will be to use in vivo mouse models, ex vivo, and in vitro assays to explore mediators of inflammation and vascular disease associated with TBI. Aim 1 will determine the effect of TBI on leukocyte-endothelial interactions and vascular function in atherosclerotic-prone mice.These endpoints will shed light on mechanisms related to the increased vascular risk associated with TBI. Aim 2 will explore mechanism(s) by which TBI promotes atherosclerosis by characterizing inflammatory responses, measuring catecholamines, and testing effects of adrenergic antagonists on vascular endpoints. Aim 3 will determine the role of downstream mediators, p-selecting glyocoprotein ligand-1, interleukin-1 receptor, and neutrophil extracellular traps (NETs) on myeloid activation and atherosclerosis induced by TBI, as these factors could serve as therapeutic targets.

目的：创伤性脑损伤（TBI）是退伍军人发病和死亡的常见原因。 在美国，估计有 530 万人患有与 TBI 相关的残疾。 通常会导致神经认知缺陷，然而，其他系统性影响也与 TBI 对心血管的影响包括应激相关的心肌病、心律失常、心电图复极变化、 和增加心脏活性氧，这些影响可能是由儿茶酚胺激增介导的。 尽管机制尚不清楚，但在一项针对美国退伍军人的 TBI 临床研究中，TBI 与 TBI 密切相关。 通过电子束计算机断层扫描测量冠状动脉钙化的严重程度， 重要的是，TBI 可能促进动脉粥样硬化形成过程。 TBI 与心血管死亡率的独立关联，与非 TBI 相比，相对风险为 2.89 对照组，即使在调整了典型的心血管危险因素之后，这些观察结果也表明了这一点。 可能是 TBI 对动脉粥样硬化的长期而有效的影响。 TBI 与全身血管变化之间的直接联系或代表其他混杂因素尚不清楚。 该应用程序的目标是确定 TBI 对血管疾病的影响并揭示潜在的 根据这些结果，将测试治疗干预措施。 试图阻止 TBI 的血管病变效应。 研究计划：为了评估 TBI 对血管疾病过程的影响，将使用 TBI 小鼠模型 确定脑损伤对交感神经活动、血管功能、白细胞内皮细胞的影响 将测量生物标志物和可能的介质的相互作用和发展。 通过流式细胞术、液相色谱法与串联质谱法、ELISA 的组合， 磁共振成像和组织学分析旨在阻止候选者的激活。 TBI 后肾上腺素能和下游细胞因子触发的炎症途径将使用以下方法进行测试 相关血管终点。 方法：实现目标的策略是使用体内、离体和体外小鼠模型 探索与 TBI 相关的炎症和血管疾病介质的检测将确定目标 1。 TBI 对易患动脉粥样硬化的白细胞-内皮相互作用和血管功能的影响 这些终点将揭示与 TBI 相关的血管风险增加的相关机制。 目标 2 将通过表征炎症来探索 TBI 促进动脉粥样硬化的机制 反应，测量儿茶酚胺，并测试肾上腺素能拮抗剂对血管终点的影响。 目标 3 将确定下游介质的作用，p-选择糖蛋白配体-1、白细胞介素-1 受体和中性粒细胞胞外陷阱（NET）对TBI诱导的骨髓激活和动脉粥样硬化的影响， 因为这些因素可以作为治疗目标。