Investigating the metabolic and epigenetic basis of the immediate and persistent state of systemic immuneparesis following traumatic injury

研究创伤后全身免疫麻痹的即时和持续状态的代谢和表观遗传基础

基本信息

  • 批准号:
    MR/X007243/1
  • 负责人:
  • 金额:
    $ 165.11万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2023
  • 资助国家:
    英国
  • 起止时间:
    2023 至 无数据
  • 项目状态:
    未结题

项目摘要

Owing to advancements in medical care, more victims of major trauma (e.g. road traffic accidents and stabbings) now reach hospital alive and survive life-saving operations. However, these survivors are at an increased risk of developing hospital-acquired infections (HAI), with >50% experiencing at least one infection during their hospital stay. The immediate clinical and economic impact of HAI are profound, with in-hospital mortality rates, length of hospital stay and inpatient costs all significantly higher in patients with HAI. Furthermore, survivors of HAI report poorer physical recovery, suffer from recurrent infections, require a greater degree of home care and are less likely to return to work. Thus, alongside the immediate and sustained health complications for patients, HAI place an increased economic burden on society.The immune system is the body's defence against infection, protecting us from harmful pathogens such as bacteria and fungi. Traumatic injury results in a significant reduction in the function of the immune system. This suppression, which occurs within minutes of the injury being sustained, is a major factor contributing to the increased susceptibility of trauma patients to HAI. However, despite this clinical impact, we currently know very little about the mechanisms that cause this decline in immune function and how quickly they occur. Identifying these mechanisms is crucial if new therapies for restoring immune function post-trauma are to be developed. Two processes are essential for immune cells to function. Firstly, they require energy, which they generate by a process called immunometabolism. Secondly, they must make and release molecules that alert the body to the presence of a pathogen. This step involves the immune cell making changes to the appearance of its DNA, and is termed epigenetics. When defects occur in either of these processes, immune cell function is reduced. Thus, could the immune suppression that develops post-trauma, and the high incidence of HAI amongst trauma patients, be explained by injury-induced changes in the processes of immunometabolism and epigenetics? To date, no study has investigated this question.Via a unique collaboration with critical-care paramedics, I work at the only UK research centre that has 24/7 access to blood samples obtained from trauma patients at the scene of their injury. These blood samples are acquired within 1-hour of injury, the so-called "Golden Hour", from patients that have sustained a traumatic brain injury (TBI) or an injury to their body. By analysing these samples, alongside blood samples that will be obtained from patients during their hospital stay (4-12 and 48-72 hours post-injury), on their day of hospital discharge, and 3 months post-injury, this project aims to examine the immediate and long-term impact of trauma on the processes of immunometabolism and epigenetics. I propose that trauma negatively effects both of these processes, resulting in impaired immune responses. To test this, I will compare the energy production and DNA profiles of immune cells isolated from trauma patients to those of healthy volunteers. Accompanying these studies will be experiments in an animal model of moderate TBI which also results in immune compromise. Providing me with samples of bone marrow, the site of immune cell production, this model will allow me to investigate whether any changes detected in the DNA profiles of circulating immune cells post-trauma originate during their formation in the bone marrow, or occur in the bloodstream post-injury. New therapies are urgently required for the treatment of HAI in trauma patients. To develop these, our understanding of injury-induced immune suppression must improve. By investigating how trauma impacts upon cellular processes that are critical for immune function, this project will yield new data that could assist in the development of novel therapies to prevent HAI post-trauma.
由于医疗保健的进步,现在有更多的重大创伤(例如道路交通事故和刺伤)受害者活着到达医院,并在挽救生命的手术中幸存下来。然而,这些幸存者发生医院获得性感染(HAI)的风险增加,50%的人在住院期间至少经历过一次感染。HAI的直接临床和经济影响是深远的,住院死亡率、住院时间和住院费用都明显高于HAI患者。此外,HAI幸存者报告身体恢复较差,患有复发性感染,需要更大程度的家庭护理,并且不太可能重返工作岗位。因此,除了给患者带来直接和持续的健康并发症外,HAI还增加了社会的经济负担。免疫系统是人体抵御感染的防御系统,保护我们免受细菌和真菌等有害病原体的侵害。创伤性损伤会导致免疫系统功能的显著下降。这种抑制发生在持续损伤的几分钟内,是导致创伤患者对HAI易感性增加的主要因素。然而,尽管有这种临床影响,我们目前对导致免疫功能下降的机制以及它们发生的速度知之甚少。如果要开发恢复创伤后免疫功能的新疗法,确定这些机制至关重要。两个过程对免疫细胞的功能至关重要。首先,它们需要能量,而能量是通过免疫代谢过程产生的。其次,它们必须制造并释放分子,提醒身体注意病原体的存在。这一步涉及到免疫细胞改变其DNA的外观,被称为表观遗传学。当这些过程中的任何一个发生缺陷时,免疫细胞的功能就会降低。因此,创伤后发生的免疫抑制和创伤患者HAI的高发是否可以用损伤诱导的免疫代谢和表观遗传学过程的变化来解释?到目前为止,还没有研究调查过这个问题。通过与重症护理护理人员的独特合作,我在英国唯一的研究中心工作,该中心可以全天候获取创伤患者在受伤现场采集的血液样本。这些血液样本是在受伤后1小时内,即所谓的“黄金时间”,从遭受创伤性脑损伤(TBI)或身体损伤的患者身上采集的。通过分析这些样本,以及将在患者住院期间(受伤后4-12小时和48-72小时)、出院当天和受伤后3个月获得的血液样本,该项目旨在研究创伤对免疫代谢和表观遗传学过程的即时和长期影响。我认为创伤对这两个过程都有负面影响,导致免疫反应受损。为了验证这一点,我将比较从创伤患者和健康志愿者身上分离出来的免疫细胞的能量产生和DNA图谱。伴随这些研究的将是中度脑外伤动物模型的实验,这也会导致免疫损害。这个模型为我提供了骨髓样本,骨髓是免疫细胞产生的地方,它将使我能够研究创伤后循环免疫细胞DNA谱中检测到的任何变化是源于骨髓中形成的,还是发生在损伤后的血液中。迫切需要新的治疗方法来治疗创伤患者的HAI。为了发展这些,我们对损伤诱导的免疫抑制的理解必须提高。通过研究创伤如何影响对免疫功能至关重要的细胞过程,该项目将产生新的数据,有助于开发预防创伤后HAI的新疗法。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The immune suppressive properties of damage associated molecular patterns in the setting of sterile traumatic injury.
  • DOI:
    10.3389/fimmu.2023.1239683
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Horner, Emily;Lord, Janet M.;Hazeldine, Jon
  • 通讯作者:
    Hazeldine, Jon
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Jon Hazeldine其他文献

University of Birmingham Cystatin D (CST5)
伯明翰大学胱抑素 D (CST5)
  • DOI:
    10.1038/scibx.2009.1142
  • 发表时间:
    2008
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Lisa Hill;V. Pietro;Di;Jon Hazeldine;David Davies;E. Toman;Ann Logan;Antonio Belli
  • 通讯作者:
    Antonio Belli
Innate immunesenescence: underlying mechanisms and clinical relevance
  • DOI:
    10.1007/s10522-014-9514-3
  • 发表时间:
    2014-07-10
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    Jon Hazeldine;Janet M. Lord
  • 通讯作者:
    Janet M. Lord

Jon Hazeldine的其他文献

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