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

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.

Spinal cord injury (SCI) can result in severe and lifelong disability, with profound social, health and economic consequences. With an estimated 4 million people worldwide living with SCI, healthcare costs among the highest of any medical condition, and no regenerative or disease-modifying therapies available to SCI patients, it remains a severe unmet need. There is an urgent need for innovative approaches to understand the molecular and cellular processes that underlie the chronic tissue pathology that is intractable to repair. Chronic dysregulated inflammation, tissue scarring and maladaptive changes in the extracellular matrix are central pathological processes responsible for the failure of tissue repair and functional recovery following traumatic SCI. Yet these processes are still poorly understood. In this translational project we will utilise multidisciplinary and complementary expertise to study how distinct inflammatory mechanisms affect extracellular matrix synthesis and fibrotic tissue remodelling after SCI. Our collaborative network (SCI-NET) will combine basic science and clinical approaches together with innovative proteomics technology to: a) characterize how intrinsic pattern-recognition inflammatory mechanisms affect matrix synthesis and proteolytic remodelling after SCI, b) identify novel cellular and extracellular bioactive proteins in SCI tissue and c) identify novel bioactive mediators with diagnostic and therapeutic potential for human SCI. The SCI-NET Consortium will examine the role of inflammatory activation on tissue remodelling and scarring in clinically relevant rat (Bradbury group) and mouse (David group) models of SCI, while the presence of endogenous alarmins will be assessed for the first time in human SCI plasma and cerebrospinal fluid (Schwab group). Advanced proteomics analysis (Schlapbach group) will characterize changes in the extracellular proteome related to alarmin signalling in rodent SCI tissues and human samples.

Health and Clinical Impact: one of our key aims in this proposal is to identify novel therapeutics and potential diagnostic biomarkers for human SCI. Although new drug development will not occur within the time frame take of this funding scheme, we expect our work to identify new targets that can be developed further in the future. This is a key advantage of our high-throughput and bioinformatics approach ensuring the analysis and filtering of multiple potential interesting molecules. Moreover, our project ensures the stringent validation and mechanistic analysis of high-throughput-derived targets prior to further pre-clinical or diagnostic studies. We ultimately hope that our research will lead to novel therapies that will improve tissue pathology and restore useful function to patients with traumatic spinal cord injuries and improve the quality of life for this patient population for which there is currently no cure and no regenerative therapies.