Roadmap for Intestinal Regeneration

总结 消化系统疾病每年影响数百万美国人，其中相当多的人将死于消化系统疾病。 这些疾病的罪魁祸首是细胞内稳态控制机制被破坏， 缺乏修复机制。修复机制在自然事件后的愈合中起着重要作用 会损伤消化道和胃肠道手术后。因此，再生能力 肠组织可能是重要的治疗工具。尽管在这方面取得了进展， 脊椎动物消化道腔层的再生，很少有人知道再生 其他细胞和组织层或整个器官。部分问题在于脊椎动物中， 细胞或组织层具有有限的再生能力。 该建议使用一种新的模型系统，棘皮动物，研究肠道再生。之间 后口动物，棘皮动物包括一些最接近的亲属脊椎动物，有惊人的 再生能力。其中一种生物，海参Holothuria glaberrima， 在消化道自我切割后，它们天生具有再生整个消化道的能力。 目前的建议是寻找建立细胞机制的作用及其潜在的 H.光裂肠信号通路和候选者 转录因子基因将在体内和体外通过基因敲低被探测， 以确定它们参与肠道再生。所获得的数据将纳入我们的 基因/细胞网络，解释细胞事件的逐步激活。另外的实验 将定义在正常和再生肠中发现的细胞群。这些实验将 用于进一步鉴定与肠上皮细胞中的早期再生事件相关的细胞/基因， 再生 我们的研究结果可以作为开发新的治疗方法/药物的基础， 再生过程它们还将为其他研究领域提供重要信息，包括 伤口愈合、免疫学、细胞生物学、基因组学和遗传学。最后，这些结果 实验将使我们更接近于更好地理解再生过程。

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.