Integrated proteomic and systems biology approach to understanding injured spinal cord pathophysiology and repair
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Spinal cord injury (SCI) is a severe neurological condition. There are currently no effective treatment options to restore function following SCI. The major obstacle to developing effective therapies is the fragmented state of our understanding of the complex SCI pathophysiology, its response to potential interventions (e.g. biomaterial therapy) and the differential response to lesion between regenerative and non-regenerative SCI models. To develop mechanisms based therapeutic approaches to spinal cord repair more objective, quantitative, and uniform measures of various pathological and regenerative events triggered by SCI are needed. To address these issues, a multi-model in vivo experimental SCI paradigm was established and compared in this thesis. To study the stimulated repair process as a function of a potential intervention, a biomimetic-aligned collagen hydrogel bridge was developed and tested in a rat SCI model. To study the natural repair process, an injury-induced regenerative paradigm, corresponding to SCI in the regenerative stage of Xenopus was established and characterized. To study the pathophysiological response, an injury-induced degenerative paradigm corresponding to SCI in the non-regenerative stage of Xenopus and in the rat model was employed. This enabled to systematically profile proteome dynamics during natural repair, stimulated repair and degeneration of the spinal cord. Bioinformatics analysis revealed unique protein subsets specifically enriched in each experimental paradigm providing a rich resource of molecular targets for functional validation and for designing new therapeutic strategies. By integrating multiple protein expression datasets and using systems biology tools, molecular and cellular processes that govern repair and pathophysiological response post-SCI were assembled into a framework to provide a holistic view. The systems biology analysis revealed that cellular proteome and metabolic reprogramming is an early response to injury in the regenerative model. The non-regenerative SCI models fail to regulate similar response upon injury. On the other hand, notable parallels between the non-regenerative models across the species were revealed, including strong enrichment of lipid metabolism, activation of lipid accumulation and inflammatory response and suppression of autophagy (an evolutionary conserved mechanism essential for lipid homeostasis) and lipophagy (autophagic degradation of lipid) representing co-ordinated molecular pathological events. Lipids such as cholesterol were identified as the potential regulatory factors underlying maladaptive inflammatory response in the non-regenerative SCI model. The absence of these events during natural repair process suggest their major role in driving pathophysiological response post-SCI. Thus, the integrative analyses converged on an evolutionarily conserved set of biological processes associated with SCI pathophysiology. Finally, these objective measures of pathological events from protein expression data also revealed that incorporation of aligned collagen hydrogel bridges into the SCI microenvironment attenuates the neurodegeneration and microglial activation and responds to injury-induced lipid accumulation by activating proteins (APOE), biological function (lipid efflux) and pathway (LXR/RXR activation in macrophages) involved in lipid homeostasis and anti-inflammation. The unexpected link between lipid metabolism, lipid accumulation and autophagy and tissue degeneration provides new leads for the development of therapeutic targets for improving spinal cord repair.
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