Roadmap for Intestinal Regeneration

摘要 消化系统疾病每年影响数百万美国人，其中相当一部分人将死于消化系统疾病。 这些疾病的主要罪魁祸首是体内平衡控制的细胞机制被破坏，以及 修复机制不完善。修复机制在自然事件后的康复中发挥着重要作用 这会损害消化道和胃肠道手术后的健康。因此，再生的能力 肠道组织可能是一种重要的治疗工具。尽管在这方面已经取得了进展 脊椎动物消化道管腔层的再生，人们对再生知之甚少 其他细胞和组织层的，或器官整体的。问题的一部分是在脊椎动物中，这些 细胞或组织层的再生能力有限。 这项建议使用了一种新的模型系统，棘皮动物，来研究肠道再生。其中 后口动物，棘皮动物包括一些与脊椎动物最接近的近亲，它们拥有令人惊叹的 再生能力。其中一种生物，海参，拥有 自体切除后再生整个消化道的先天能力。 本提案试图确定细胞机制的作用及其基础 板栗肠再生的分子基础研究。信号通路和候选信号 转录因子基因将通过体内和体外的药理学和基因敲除来探测， 以确定它们与肠道再生的关系。所获得的数据将纳入我们的 基因/细胞网络，解释了细胞事件的逐步激活。额外的实验 将定义在正常和再生肠道中发现的细胞群。这些实验将 用于进一步确定与肠道早期再生事件相关的细胞/基因 再生。 我们的结果可以作为开发新的疗法/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、基因组学和系统发育学。最后，这些措施的结果 实验将使我们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.