: There is evidence that functional recovery after spinal cord injury is not only related to the magnitude of the initial trauma but to complex secondary factors that cause additional damage to neighboring, intact cord tissue. Our general hypothesis is that the serine protease, thrombin, acting through its protease activated receptors (PARs), is one such factor that participates in secondary pathogenesis in the traumatized spinal cord. The following experiments will test our 3 major hypotheses: Hypothesis 1: Increased expression of thrombin after spinal cord injury contributes to blood-spinal cord barrier breakdown to proteins, promotes the acute inflammatory response, and limits locomotor recovery. Experiments: We will compare thrombin activity, neutrophil and macrophage infiltration, blood-spinal cord barrier permeability and locomotor recovery in spinal cord injured mice treated with either a thrombin antagonist or vehicle. Quantitative light and ultrastructural studies will detail white matter pathology and define those cells that express prothrombin and its natural inhibitor protease nexin-1. Hypothesis 2: Thrombin modulates barrier disruption and the early inflammatory response through its PAR-1 receptor. Experiments: We will compare blood-spinal cord barrier permeability, neutrophil and macrophage infiltration, white matter pathology, and locomotor recovery in spinal cord injured PAR-1 nulls and wild-type littermates. In addition, we will determine the extent to which PAR-1, expressed by the circulating monocytes/macrophages, is necessary for their infiltration into the traumatized spinal cord. Hypothesis 3: Thrombin, via the PAR-1 receptor, modulates wound healing after spinal cord injury by promoting the formation of an astrocytic scar, collagen deposition and revascularization. Experiments: Quantitative immunocytochernistry will be used to determine the extent to which wound healing is dependent on the PAR-1 receptor in PAR-1 nulls and wild-types. Together, the proposed studies offer the first comprehensive evaluation of thrombin in the injured spinal cord and establish an important foundation for defining improved therapies for the spinal cord injured patient.
| Weinzierl, Martin; Mautes, A E; Whetstone, William et al. (2004) Endothelin-mediated induction of heme oxygenase-1 in the spinal cord is attenuated in transgenic mice overexpressing superoxide dismutase. Brain Res 1030:125-32 |
