Abstract –(Of the parent grant NIH award 1R21AG0577974 “Balancing degeneration and regeneration in the echinoderm nervous system”) The capacity to regenerate the central nervous system of adult mammals, including humans, is highly limited. This is why loss of functions, following injuries or neurodegenerative diseases, impair the organisms for the rest of their life. In contrast to mammals, other animals have various degrees of regenerative abilities. Among deuterostomes, echinoderms are known for their amazing repair and regeneration mechanisms. This proposal uses an echinoderm, as a novel model system, to study nervous system regeneration. This organism, the sea cucumber Holothuria glaberrima, possesses the innate ability to regenerate components of its central nervous system following injury or autotomy. The present proposal searches to establish the role that three cellular mechanisms (cell dedifferentiation, cell proliferation and cell death) play in the balance between degeneration and regeneration. Cellular mechanisms will be analyzed using pharmacological and molecular tools. The experimental strategy takes advantage of a recently established culture system for nervous system explants and on the ability to trigger dedifferentiation by electroporation. Additional experiments are aimed at identifying the underlying molecular bases of nervous system regeneration. The gene expression profile of normal and regenerating nervous components will be compared and used to identify the genes associated with the process of nervous system regeneration. Our results could serve as the basis for the development of new therapeutics/drugs that modulate regenerative processes. They will also provide important information to other fields of research, including wound healing, immunology, cell biology, genomics and phylogenetics. Finally, the outcome of these experiments will bring us closer to a better understanding of regenerative processes in general.

Narrative The present project focus on a novel model system, and echinoderm with amazing regeneration capacities, to elucidate the role of cellular dedifferentiation, cellular proliferation and cell death in the process of nervous system regeneration. The results will provide important comparative data on the cellular and molecular events that mediate the balance between degeneration and regeneration and that allows for the dramatic regenerative process observed in these organisms.