Traumatic Brain Injury and Vascular Disease

创伤性脑损伤和血管疾病

• 批准号: 10347179
• 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/10347179
• 关键词: 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; 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; Lead; Leukocytes; Ligands; Light; Link; Liquid Chromatography; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; 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; base; 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：颅脑损伤是导致退伍军人发病和死亡的常见原因。 在美国，估计有530万人患有与脑外伤相关的残疾。TBI 通常会导致神经认知障碍，然而，其他系统效应也与 TBI。心血管效应包括应激性心肌病、心律失常、心电复极改变、 并增加心脏活性氧的含量。这些影响可能是由儿茶酚胺激增所介导的， 虽然机制(S)尚不清楚。在一项对美国退伍军人的脑损伤的临床研究中，脑损伤与 根据电子束计算机断层扫描测量的冠状动脉钙化的严重程度， 提示脑外伤可能促进动脉粥样硬化形成过程。重要的是，有一个明显的 脑外伤与心血管死亡率的独立关联，与非脑损伤相比，相对危险度为2.89 对照组，即使在调整典型心血管危险因素后也是如此。这些观察表明 这可能是脑外伤对动脉粥样硬化的一种慢性而有效的影响。然而，无论这些发现是否代表着 脑外伤与全身血管改变或代表其他混杂因素之间的直接联系尚不清楚。这个 这项应用的目标是确定脑外伤对血管疾病的影响，并揭示潜在的 造成这些影响的机制。根据这些结果，治疗干预措施将在 试图阻断脑外伤的血管病变效应。 研究计划：为了评估脑外伤在血管疾病过程中的作用，将使用脑外伤的小鼠模型 探讨脑损伤对交感神经活性、血管功能、白细胞内皮细胞的影响 相互作用与动脉粥样硬化的发展。生物标志物和可能的介体将被测量 通过流式细胞仪，液-质联用，酶联免疫吸附试验， 磁共振成像和组织学分析。旨在阻止候选人激活的治疗方法 脑外伤后肾上腺素能和下游细胞因子触发的炎症通路将使用 相关的血管终点。 方法：实现这些目标的策略将是使用体内、体外和体外的小鼠模型。 探索与脑外伤相关的炎症和血管疾病的介质。目标一号将决定 颅脑损伤对动脉粥样硬化易感人群白细胞-内皮细胞相互作用及血管功能的影响 这些终点将阐明与脑外伤相关的血管风险增加相关的机制。 目的2探讨脑外伤致动脉粥样硬化的炎症机制(S) 对血管终点的反应、儿茶酚胺的测量和肾上腺素能拮抗剂的效果测试。 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 受体和中性粒细胞外陷阱(Net)在脑损伤后髓系激活和动脉粥样硬化中的作用 因为这些因素可以作为治疗的靶点。