This is an established clinical spinal cord injury research center. Four research projects and a core facility are proposed. Project 1 (Experimental Therapy) will examine the time course and relationships of tissue ionic and phosphate shifts to traumatic injury. Three hypotheses will be tested: that phosphates released by lipid peroxidation bind Ca ions and cause the depression of extracellular Ca activity observed in injured spinal cords, that the fall in extracellular Ca activity protects neurons, and that return of extracellular Ca causes secondary tissue damage due to excessive Na/Ca exchange. Treatments stemming from the hypotheses will be assessed. Project 2 (Extracellular Ionic and pH Regulation) will investigate the mechanisms of extracellular ionic changes in acute and chronic injured spinal cords. Ion-selective microelectrodes will be used to determine the extent to which extracellular Na, K, Ca, and Cl ionic changes are due to equilibration and are prolonged due to extracellular space constriction, and to ascertain whether acid production and tissue injury are governed by ischemia and serum glucose levels. Project 3 (Axonal Dysfunction) will study axon conduction in dorsal columns of injured spinal cords, utilizing a new random double pulse stimulation method to characterize supernormal behavior, fatigue, and refractory period in injured and demyelinated axons after spinal cord contusion and compression. The experiments will test the hypotheses that injured axons release more K ions and are more sensitive to extracellular K ionic activity changes. Project 4 (Recovery of Motor Dysfunction) will characterize changes in lumbosacral segmental excitability and interactions of residual descending tract activity with these segmental changes after spinal cord injury, focussing on the the effects of 4-aminopyridine, a blocker of voltage-sensitive K channels, on axonal conduction and segmental excitability. The Core Facilities will support the research effort in the center by providing basic histological and physiological services, and animal care support. Positions for a clinical and a laboratory spinal cord injury fellow are requested the aim of training independent investigators in clinical and basic research on spinal cord injury. The overall goals of this Center are to elucidate mechanisms of axonal loss and dysfunction in spinal cord injury and to establish a rational basis for treatments of spinal cord injury.
