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

脊髓损伤(SCI)可能对受影响的人的生活产生毁灭性的影响。它通常是道路交通事故、职业和体育事故以及暴力行为造成的严重创伤造成的。脊髓损伤经常导致部分或完全瘫痪，限制患者独立执行简单的日常功能(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，仍然没有足够的治疗脊髓损伤的方法。从病理学上讲，脊髓损伤的特点是损伤部位的慢性炎症和组织损伤，这些损伤不能愈合或再生。缺乏愈合会导致组织结构发生剧烈变化，形成纤维性瘢痕组织。我们最近发现，参与组织疤痕形成的分子(或蛋白质)与慢性炎症之间存在联系，构成疤痕组织的蛋白质可以引起并放大炎症。这会导致长期的炎症反应，不允许积极的组织再生和愈合。负责这一反应的分子尚不清楚，机制也不清楚。在这里，我们的国际联盟(SCI-Net)将合作了解这一病理过程，并将测试一种旨在阻止这种持续的局部炎症并促进伤口积极愈合的治疗方法。为此，我们将使用啮齿动物模型，准确复制人类脊髓损伤的病理特征以及来自脊髓损伤患者的临床人类样本。在我们的临床前动物模型中，我们将确定驱动炎症和瘢痕形成的分子和机制，并确定是否可以从药物上阻止这些分子和机制，以改善修复反应。人体样本将被用来发现疾病的新诊断标记和可能的治疗目标，重点是破坏永久性炎症和纤维化。为了最大限度地增加我们的发现机会，我们将使用一种名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，在受伤后会发生巨大变化。使用这些创新的方法，我们希望做出新的发现，改变我们对脊髓损伤的病理和修复损伤脊髓的过程的理解，最终这些数据可能会导致新的治疗方法来改善脊髓损伤患者的功能结局。

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.