2004 Directors' Summary Synopsis

OVERCOMING INHIBITION TO PROMOTE REGENERATION

Regeneration of axons in the adult central nervous system is limited because of the presence of inhibitory proteins and molecules. As inhibitors have been identified, several Miami Project investigators have gained knowledge that may lead to treatment strategies to block inhibitors.

One major inhibitory protein family is the chondroitin sulfate proteoglycans (CSPGs). Proteoglycans, made up of proteins and sugar chains, have been shown to form a physical barrier that leads to reduced axon regeneration. Previous research has shown that if the sugar portions of the proteoglycan are eliminated with an enzyme Chondroitinase ABC, axon regeneration improves. While this experimental strategy does improve regeneration, the axons do not regenerate beyond the injury area. Knowing that Chondroitinase ABC does not completely "digest" the sugar chains, Dr. Barbara Grimpe, formerly from Case Western Reserve University, has developed a new strategy to more completely inhibit the formation of sugar chains on proteoglycans. Using a totally new DNA enzyme technology, she and her colleagues found that regenerating axons could indeed bypass the injury area in experimental SCI.

Agrin and NOGO are other inhibitory proteins. This year, Dr. John Bixby studied Agrin and Dr. John Bethea studied NOGO. Both reported on work done in their laboratories that is helping to understand the biological structure of these proteins. In the course of his study, Dr. Bethea found that regeneration was increased after blocking NOGO with specific antibodies.

Several strategies have been proposed that modify the environment within the spinal cord to promote regeneration. For example, the study by Drs. Mary Bartlett Bunge and Damien Pearse described previously utilized drugs to increase the levels of the cell-signaling molecule cyclic AMP. When cyclic AMP levels are normal, axons seem to navigate the inhibitory environment better. Another approach to overcome the inhibitory environment in the injured spinal cord is to increase the concentration of growth promoting factors and provide a supportive area for growth. In chronic spinal cord injuries that result in substantial nervous tissue loss, it may be necessary to implant tubular guidance scaffolds to help reconnect the spinal cord on each end of the injury. A strategy that Dr. Martin Oudega examined this year is the use of freeze-dried porous guidance scaffolds that have been impregnated with brain-derived neurotrophic factor (BDNF). BDNF is a growth factor known to promote cell survival. In future studies, he has plans to combine these scaffolds with cell transplantation approaches such as Schwann cells or olfactory ensheathing cells in an effort to promote sufficient regeneration.