DESCRIPTION (provided by applicant): The lack of an efficient repair mechanism that includes defective fiber growth or limited neurogenesis is the basis for many diseases or malfunctions of the nervous system. Consequently, the capacity to improve healing and/or regeneration processes in the nervous system has profound therapeutic, as well as economical consequences. We have pioneered the use of a novel model system to study nervous system regeneration, The echinoderm Holothuria glaberrima. This species can regenerate both its radial nerve cord and enteric nervous system in a process that includes re-growth of nerve fibers and neurogenesis. Echinoderms are closely related to vertebrates, thus, the study of cellular and molecular processes in this system can serve to illuminate the mechanisms involved in nervous system regenerative processes in humans. In the present proposal we focus on several proteins that are involved in nervous regenerative events. These include: (1) Orpin, a novel protein characterized from the holothurian, (2) melanotransferrin, a protein found in many chordates but whose function remains elusive, and (3) two well-known signaling pathways, Wnt and retinoic acid, that have been shown to be associated with nervous system development in other species. The study of these molecules will address various steps in the regeneration of the nervous system, including nerve cell differentiation and proliferation, apoptosis and nerve-dependency of organ regeneration. We propose experiments that include in vivo and in vitro manipulations to determine the protein and mRNA temporal and spatial expression patterns, as well as the protein function. The expected results will help understand the molecular mechanisms that underlie the amazing regeneration of the nervous system in holothurians and will provide important cues on how this regeneration might be achieved in humans.

The present project involves the use of an echinoderm, the sea cucumber Holothuria glaberrima, as a novel model to study regenerative processes. It focuses on understanding the molecular mechanisms needed for nervous system regeneration. The lack of, or limitations of nervous system regeneration in humans are the basis of many diseases or problems following damage. H. glaberrima can regenerate its central and enteric nervous components, a process that involves both neurogenesis and fiber regeneration. Moreover, echinoderms are deuterostomes, thus are closely related to vertebrates. This proposal builds upon the large amount of data that has been acquired by the P.I. over the last decade and in particular on recent molecular findings associated with nervous system regeneration. The outcome of our experiments will characterize the expression and possible function of several genes and their protein products associated with nervous system regeneration. Moreover, the project provides a venue for the training of graduate and undergraduate students, many of them from underrepresented minorities. The results will provide important information on the steps and cellular events that allow the dramatic regeneration process observed in holothurians but not found in vertebrates.