Role of Fibroblasts in Axon Regeneration after SCI

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DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in formation of scar tissue that is a potent barrier to axon regeneration. This scar is comprised of excess deposition of extracellular matrix (ECM) molecules in both rodents and humans. Why most axons fail to grow into this ECM-rich region is not fully understood. In vitro assays have implicated fibroblasts as a major source of inhibitory ECM molecules, but whether this also true in vivo is not clear. While the meninges were thought to be the primary source of fibroblasts after SCI, recent evidence indicates that the perivascular niche could be an alternative source of the scar tissue. The overall goal of this proposal is to determine the role of perivascular fibroblasts in scar formation in order to promote axon regeneration after contusive SCI by pursuing the following aims: 1) Determine the temporospatial distribution and the cellular fate of fibroblasts after contusive SCI 2) Determine the effect of fibroblast ablation on scar formation and axon regeneration after SCI. 3) Determine the role of fibroblast PDGFR-¿ on scar formation and axon regeneration after SCI. Our proposed studies will fill a gap in knowledge about the role of fibroblasts in animal models of SCI and may reveal new therapeutic targets to treat SCI patients. PUBLIC HEALTH RELEVANCE: Patients with spinal cord injury (SCI) suffer from permanent disabilities but have limited treatment and therapeutic options. A major reason for the permanent deficits is the inability of axons in the spinal cord to regenerate through the scar tissue that develops at the injury site. Fibroblasts have been implicated as a major component of this scar tissue, but there have been limited animal studies directly addressing this issue. We will use genetics and pharmacology in animal models to test whether targeting fibroblasts can reduce scarring and promote axon regeneration and functional recovery after SCI.