The role and regulation of deep crypt secretory cells in colitis

项目总结 深隐窝分泌细胞(Dcs)是存在于结肠隐窝中的一种未被研究的分泌细胞系。 在结肠炎中扮演未知角色的碱基。在初步数据中，我显示了DCs细胞表达一类已知的蛋白质 作为宿主防御肽(HDPs)，可影响关键上皮细胞(如分化、屏障完整性)和 免疫功能。尽管有明显的结肠分泌细胞数量和HDP水平的改变 炎症性肠病(IBD)，对DC细胞和HDP的调节机制知之甚少。 这项建议旨在确定驱动DCs细胞分化和HDP的机制 结肠炎的产生，并确定这些因素在调节上皮和免疫中的作用 功能。使用具有升高的DCs细胞数量的小鼠模型，我建议在体内和在 体外方法了解DCs细胞分化和HDP表达的机制 结肠(目标1)，并测试改变的dcs细胞来源的hdp如何影响结肠内稳态和急性和 慢性结肠炎严重程度(目标2)。这项工作将在高级阶段获得新的专业知识后完成 结肠炎模型的转录研究和上皮谱系追踪--与我的共同导师团队合作 和咨询委员会。这项工作将促进我们对驱动细胞机制的理解 结肠炎的肠上皮重塑，从而可能为IBD和 其他肠道炎症性疾病。研究和职业发展计划，与 我的导师和咨询委员会将提供必要的培训和支持，以成为 学术研究机构的独立研究员。

PROJECT SUMMARY Deep crypt secretory (DCS) cells are an understudied lineage of secretory cells residing in the colonic crypt base with unknown roles in colitis. In preliminary data, I show that DCS cells express a class of proteins known as host defense peptides (HDPs) that can influence key epithelial (e.g. differentiation, barrier integrity) and immune functions. Despite clear demonstrations of altered colonic secretory cell numbers and HDP levels in inflammatory bowel disease (IBD), the mechanisms regulating DCS cells and HDPs are poorly understood. This proposal is designed to identify the mechanisms driving DCS cell differentiation and HDP production in colitis, and determine the role of these factors in regulating epithelial and immune functions. Using a mouse model with elevated DCS cell numbers, I am proposing coordinated in vivo and in vitro approaches to understand the mechanisms underlying DCS cell differentiation and HDP expression in the colon (Aim 1) and to test how altered DCS cell-derived HDPs affect colonic homeostasis and acute and chronic colitis severity (Aim 2). This work will be accomplished with new expertise obtained in advanced transcriptomic studies and epithelial lineage tracing in models of colitis by working with my team of co-mentors and advisory committee. This work will advance our understanding of the cellular mechanisms that drive intestinal epithelial remodeling in colitis, and thus may reveal new potential therapeutic targets for IBD and other intestinal inflammatory disease. The research and career development plan, generated in concert with my mentors and advisory committee, will provide the training and support necessary to become an independent investigator at an academic research institution.