The role and regulation of deep crypt secretory cells in colitis

项目摘要 深隐窝分泌（DCS）细胞是一个研究不足的谱系分泌细胞居住在结肠隐窝 在结肠炎中的作用未知。在初步数据中，我表明DCS细胞表达一类已知的蛋白质， 作为宿主防御肽（HDPs），可以影响关键上皮细胞（例如分化、屏障完整性）， 免疫功能。尽管结肠分泌细胞数量和HDP水平的改变清楚地表明， 对于炎症性肠病（IBD），调节DCS细胞和HDP的机制知之甚少。 该建议旨在确定驱动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 功能协调发展的使用DCS细胞数量增加的小鼠模型，我建议在体内和体内协调 体外方法来了解DCS细胞分化和HDP表达的机制， 结肠（目的1），并测试改变的DCS细胞衍生的HDPs如何影响结肠稳态和急性和 慢性结肠炎严重程度（目标2）。这项工作将利用先进的技术和经验来完成。 通过与我的共同导师团队合作，在结肠炎模型中进行转录组学研究和上皮谱系追踪 咨询委员会。这项工作将促进我们对细胞机制的理解， 结肠炎中的肠上皮重塑，因此可能揭示IBD的新的潜在治疗靶点， 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， 学术研究机构的独立调查员。

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.