Humans, as warm-blooded vertebrates, do not regenerate axons in their central nervous system (CNS) spontaneously. Conversely, cold-blooded vertebrates demonstrate remarkable abilities for nerve regeneration in their CNS. Studies of the molecular mechanisms of nerve regeneration have led to the discovery of several proteins that are induced during successful nerve regeneration. Analysis of the teleost fish optic nerve regeneration system led us to the identification of the RICH proteins. Several mutant versions of zebrafish RICH (zRICH) proteins have been generated and studied in our laboratory at the biochemical and cellular levels. This protein is a 2', 3'-cyclic nucleotide, 3'-phosphodiesterase that can bind to cellular membranes through a C-terminal membrane localization domain. Interestingly, our recent studies have shown that zRICH can bind to tubulin and enhance neuronal plasticity by promoting the formation of neurite branches. The central domain of the protein is sufficient for interaction with tubulin, but not for induction of neuritogenesis. One of the aims of this project is to learn additional details about the effects of zRICH in neuronal plasticity. Additional mutant versions of zRICH will be studied with our PC12 differentiation model, to learn whether the membrane localization domain or the acidic N-terminal domain play roles in neuritogenesis.
A second aim i s to explore the possibility of synergism of zRICH with other neuronal plasticity enhancing proteins such as GAP43 and CAP23. A third goal is exploring whether the plasticity enhancing effects can be applied to neural stem cells. The studies are relevant to public health by providing a better understanding of the process of nerve regeneration, and novel tools for the treatment of human diseases caused by damage to nerve fibers in the CNS, for example spinal cord injury.
Many permanent medical conditions are derived from the inability of humans to regenerate nerves in their brain and spinal cord, constituting a major public health problem. The classic example is paralysis from spinal cord injury, which afflicts over 250,000 Americans, having a tremendous impact on their quality of life. The overall goal of this project is to understand the function of proteins that promote nerve regeneration, which will provide novel targets to develop advanced treatments, with the aim of improving or even curing these medical conditions.