Traumatic Brain Injury and Vascular Disease

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TBI相关残疾。TBI 通常导致神经认知缺陷，然而，其他全身性影响也与 创伤性脑损伤心血管效应包括应激性心肌病、心律失常、ECG复极变化， 以及心脏活性氧增多这些作用可能是由儿茶酚胺激增介导的， 尽管机制尚不清楚。在一项针对美国退伍军人的TBI临床研究中， 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， 提示TBI可能促进动脉粥样硬化形成的过程。重要的是，有一个明显的 TBI与心血管死亡率的独立相关性，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后。这些观察表明， 可能是TBI对动脉粥样硬化的慢性和有效影响。然而，这些发现是否代表了 TBI和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。的 本申请的目的是确定TBI对血管疾病的影响，并揭示潜在的 负责这些影响的机制。根据这些结果，将在以下国家测试治疗干预措施： 试图阻断TBI的血管病变效应。 研究计划：为了评估TBI在血管疾病过程中的作用，将使用TBI小鼠模型 以确定脑损伤对交感神经活性、血管功能、白细胞-内皮细胞 相互作用和动脉粥样硬化的发展。将测量生物标志物和可能的介质 通过流式细胞术，液相色谱串联质谱，ELISA， 磁共振成像和组织学分析。旨在阻断候选药物激活的疗法 TBI后肾上腺素能和下游肾上腺素触发的炎症通路将使用 相关血管终点。 方法：实现目标的策略将是使用体内小鼠模型、离体和体外 本发明的目的是通过测定来探索与TBI相关的炎症和血管疾病的介质。目标1将决定 TBI对动脉粥样硬化倾向患者白细胞-内皮细胞相互作用和血管功能的影响 这些终点将阐明与TBI相关的血管风险增加相关的机制。 目的2将探讨TBI促进动脉粥样硬化的机制， 反应，测量儿茶酚胺和测试肾上腺素能拮抗剂对血管终点的影响。 目的3将确定下游介质，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诱导的骨髓活化和动脉粥样硬化的影响， 因为这些因素可以作为治疗靶点。

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.