SUMMARY Digestive diseases affect millions of Americans each year, and a significant number will die from them. The main culprits of these diseases are disrupted cellular mechanisms for homeostatic control and deficient repair mechanisms. Repair mechanisms play an important role in healing after natural events that damage the digestive tract and after gastrointestinal surgery. Accordingly, the ability to regenerate intestinal tissue could be an important therapeutic tool. Although advances have been made on the regeneration of the luminal layer of the vertebrate digestive tract, little is known about the regeneration of other cells and tissue layers or of the organ as a whole. Part of the problem is that in vertebrates, these cells or tissue layers have limited regenerative capacity. This proposal uses a novel model system, an echinoderm, to study intestinal regeneration. Among deuterostomes, echinoderms comprise some of the closest relative to vertebrates that have amazing regenerative capacities. One of these organisms, the sea cucumber Holothuria glaberrima, possesses the innate ability to regenerate their entire digestive tract after it is self- autotomized. The present proposal searches to establish the role of cellular mechanisms and their underlying molecular bases on the regeneration of H. glaberrima intestine. Signaling pathways and candidate transcription factor genes will be probed pharmacologically and by gene knockdown, in vivo and in vitro, to determine their involvement in intestinal regeneration. The obtained data will be incorporated into our gene/cellular network that explains the step-by-step activation of cellular events. Additional experiments will define the cellular populations found in normal and regenerating intestines. These experiments will serve to further identify the cells/genes associated with the early regenerative events in intestinal 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 will elucidate the role of signaling pathways and genes in the process of intestinal regeneration and will establish a roadmap of the cellular and molecular events needed for successful regeneration to occur. The project also 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 gene activation networks and the cellular populations that allow the dramatic regeneration process observed in holothurians but not found in vertebrates.