Identification of novel bioactive mediators of tissue scarring, inflammation and extracellular matrix remodeling after spinal cord injury

脊髓损伤后组织疤痕、炎症和细胞外基质重塑的新型生物活性介质的鉴定

基本信息

批准号：
MR/R005532/1
负责人：
Elizabeth Bradbury
金额：
$ 30.15万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR005532%2F1
关键词：
Identification novel bioactive mediators tissue

项目摘要

Spinal cord injury (SCI) can have a devastating impact on the life of affected individuals. It is usually the result of severe trauma following road traffic accidents, occupational and sporting accidents and acts of violence. SCI often results in partial or complete paralysis, limiting the patients' ability to perform simple daily functions independently (such as eating, washing and dressing) as well as loss of bladder, bowel and sexual function. Despite this, there are still no adequate therapies for SCI. Pathologically, SCI is characterized by chronic inflammation at the site of injury and tissue damage that does not heal or regenerate. The lack of healing causes drastic changes in the tissue structure, which becomes fibrotic scar tissue. We have recently discovered that there is a link between the molecules (or proteins) involved in tissue scarring and chronic inflammation, and that proteins that make up the scar tissue can cause and amplify inflammation. This leads to a long term inflammatory reaction and does not allow positive tissue regeneration and healing. The molecules that are responsible for this response are not yet known and the mechanism is not understood. Here, our international consortium (SCI-NET) will collaborate in order to understand this pathological process and will test a therapeutic approach that aims to block this unceasing local inflammation and promote positive wound healing. To do so, we will use rodent animal models that accurately replicate the pathological characteristics of human SCIs as well as clinical human samples from SCI patients. In our pre-clinical animal models we will identify the molecules and mechanisms that drive inflammation and scarring and determine whether we can block these pharmacologically to improve the repair response. The human samples will be used to discover new diagnostic markers of disease and possible therapy targets, focusing on the disruption of perpetual inflammation and fibrosis. To maximize our chances for discovery we will use different variations of a high-end technology called proteomics, based on state of-the-art analytical instruments that can identify and quantify thousands of proteins, the key molecules that make up our tissues and which are dramatically altered after injury. Using these innovative approaches we expect to make new discoveries that will change our understanding of the pathology of SCI and processes involved in repairing the injured spinal cord, and ultimately this data may lead to new therapies for improving functional outcome for spinal injured patients.

脊髓损伤 (SCI) 会对受影响个体的生活产生毁灭性影响。它通常是道路交通事故、职业和体育事故以及暴力行为后严重创伤的结果。脊髓损伤常常导致部分或完全瘫痪，限制患者独立执行简单日常功能（如进食、洗涤和穿衣）的能力，以及膀胱、肠道和性功能的丧失。尽管如此，仍然没有足够的 SCI 治疗方法。从病理学角度来说，SCI 的特点是损伤部位出现慢性炎症以及无法愈合或再生的组织损伤。缺乏愈合会导致组织结构发生剧烈变化，变成纤维化疤痕组织。我们最近发现，参与组织疤痕和慢性炎症的分子（或蛋白质）之间存在联系，并且构成疤痕组织的蛋白质可以引起和放大炎症。这会导致长期的炎症反应，并且不允许积极的组织再生和愈合。造成这种反应的分子尚不清楚，其机制也不清楚。在这里，我们的国际联盟 (SCI-NET) 将进行合作，以了解这种病理过程，并将测试一种治疗方法，旨在阻止这种持续的局部炎症并促进伤口积极愈合。为此，我们将使用啮齿动物模型来准确复制人类 SCI 的病理特征以及 SCI 患者的临床人体样本。在我们的临床前动物模型中，我们将确定驱动炎症和疤痕的分子和机制，并确定是否可以通过药理学来阻断这些分子和机制以改善修复反应。人体样本将用于发现新的疾病诊断标志物和可能的治疗目标，重点是破坏永久性炎症和纤维化。为了最大限度地提高发现机会，我们将使用称为蛋白质组学的高端技术的不同变体，该技术基于最先进的分析仪器，可以识别和量化数千种蛋白质，这些蛋白质是构成我们组织的关键分子，受伤后发生了巨大的变化。使用这些创新方法，我们期望取得新的发现，这将改变我们对 SCI 病理学和修复受损脊髓过程的理解，最终这些数据可能会带来改善脊髓损伤患者功能结果的新疗法。