Role of SPARC in Wound Healing After Spinal Cord Injury

PROJECT SUMMARY: Spinal cord injury (SCI) triggers a cellular and extracellular matrix (ECM) remodeling response to close the wound. This response is driven largely by astrocytes forming a protective border around infiltrating cells. This process is incomplete in most mammals, failing to restore growth promoting substrates, and leading to excessive fibrosis. Fibrosis after SCI is characterized by the secretion and deposition of ECM components (eg. collagen) and the establishment of a chronic scar, in which connective tissue replaces normal parenchyma. Conserved roles for non-neural wound healing mechanisms have been identified in the astrocyte response to SCI, but the molecular cues that drive fibrosis after SCI are not fully characterized and represent a critical gap impeding the development of strategies to improve spinal cord wound healing. The long-term goal is to develop therapies that promote wound closure and limit fibrotic processes that lead to persistent scarring. SPARC (Secreted Protein Acidic and Cysteine Rich) is a central modulator of both wound healing and fibrosis. There is a robust and persistent increase in SPARC protein expression in border-associated astrocytes after SCI and constitutive knockout of SPARC impairs wound healing and impacts both cellular and extracellular remodeling. The overall objective of this proposal is to determine the role of astrocytic SPARC signaling in the structural and functional responses to SCI. The central hypothesis is that astrocytic SPARC has an acute, early, pro-wound healing role and a sub-acute, late, pro-fibrotic role following SCI. The following two specific aims are proposed: 1) Characterize the temporal roles of astrocytic SPARC in wound remodeling following SCI; 2) Determine the effect of acute and sub-acute SPARC deletion in astrocytes on functional recovery after SCI. The approach in Aim 1 will be to target acute and sub-acute SPARC expression in astrocytes using temporal control in a conditional knockout mouse model to evaluate cellular responses and ECM composition following contusive SCI. In Aim 2, the approach will be to assess sensory and motor recovery in control and astrocyte-specific conditional knockout mice with acute or sub-acute SPARC deletion following contusive SCI. The proposed research is innovative in that it centers on defining the temporal and cell-type specificity for a key driver of epithelial wound healing and fibrosis in the context of SCI, connecting the fields of non-neural and neural wound healing. The proposed studies are significant as an understanding of conserved roles for non- neural wound healing pathways after SCI, may lead to the development of new therapeutic approaches to alter SCI progression, enhance remodeling, and limit pathological scarring. The expectation is that completion of the proposed studies will determine the role of astrocyte-derived SPARC in wound healing and fibrosis after SCI. The identification of new regulators of wound healing and fibrosis will allow for the subsequent development of therapies to increase repair by reducing the growth-restrictive environment after SCI.