Enteroendocrine cell plasticity during intestinal injury

项目摘要/摘要 这项提案的目标是确定一个五年计划，使Brian Muegge，M.D.，Ph.D. 独立内科医生-科学家，研究肠道内分泌细胞在肠道损伤中的作用。他 在华盛顿大学获得医学博士和博士学位，在那里他研究肠道微生物群。 在接受了内科和内分泌学的临床培训后，米格加入了撒迪厄斯博士的实验室 斯塔彭贝克。在那里，他发现肠道内分泌细胞在损伤过程中会发生动态变化。 增加促进肠道愈合的因子的表达。发现罕见的肠道内分泌 细胞在损伤过程中进行适应性重新编程在肠道中建立一个重要的新范式 生物学。他通过开发新的体外模型系统来扩展这些发现，以生长和损伤 肠内分泌细胞，以及分离和转录图谱的实验和分析方法 来自这些细胞的单个核。这项工作是提案中目标的基础。 这个项目的中心指导将由导师斯塔彭贝克博士提供。斯塔彭贝克博士，一位 内科医生兼科学家，是国际公认的肠道干细胞和伤口修复专家。他有一个 在培训内科医生-科学家为独立职业做准备方面有杰出的记录。此外。 Muegge博士组建了一个由内分泌学、发展学专业知识的教职员工组成的咨询委员会 生物学和核单核糖核酸测序谁将提供关键的科学和职业指导。 华盛顿大学是接受这种培训的理想场所，拥有出色的资源和专业知识 现成的。 这项建议的主要研究目标是解决肠内分泌细胞亚型如何变化的问题 它们的活动(分泌)或分化状态对伤害信号的反应。斯塔彭贝克博士的实验室已经 以前描述了肠道吸收细胞如何使用改变的、适应性的重新编程来实现 恢复上皮完整性的新表型。Muegge博士的研究首次提供了类似的证据 重编程可能发生在肠内分泌谱系中。他使用计算方法来识别 肠内分泌细胞分泌的候选调节者，并将使用新的损伤模型来验证这些假设 在体外和体内。他将确定EEC细胞和转录适应损伤的机制 单细胞RNA测序。这些努力有望从根本上改变我们对上皮细胞的理解 辨别和确定治疗慢性损伤的新靶点。这个K08奖项将提供 米格博士成为一名成功的独立调查员所需的必要资源和技能

Project Summary / Abstract The goal of this proposal is to define a 5-year plan to prepare Brian Muegge, M.D., Ph.D., to become an independent physician-scientist studying the role of intestinal enteroendocrine cells during gut injury. He obtained his M.D. and Ph.D. degrees at Washington University, where he studied the intestinal microbiome. After clinical training in Internal Medicine and Endocrinology, Dr. Muegge joined the lab of Dr. Thaddeus Stappenbeck. There he has identified that intestinal enteroendocrine cells are dynamically altered during injury to increase the expression of factors that promote intestinal healing. The finding that rare enteroendocrine cells undergo adaptive reprogramming during injury establishes an important new paradigm in intestinal biology. He has extended these findings by developing new in vitro model systems to grow and injure enteroendocrine cells, along with experimental and analytic methods to isolate and transcriptionally profile single nuclei from these cells. This work serves as the basis for the aims in the proposal. The central guidance for this project will be provided by the mentor, Dr. Stappenbeck. Dr. Stappenbeck, a physician-scientist, is an internationally recognized expert in intestinal stem cells and wound repair. He has a distinguished track record of training physician-scientists as they prepare for independent careers. In addition. Dr. Muegge has assembled an advisory committee of faculty with expertise in endocrinology, developmental biology, and single nuclear RNA sequencing who will provide crucial scientific and career guidance. Washington University is an ideal place to receive this training, with outstanding resources and expertise readily available. The primary research goal of this proposal is to address how subtypes of enteroendocrine cells change their activity (secretion) or state of differentiation in response to injury signals. Dr. Stappenbeck’s lab has previously characterized how absorptive cells of the intestine use altered, adaptive reprogramming to achieve new phenotypes that restore epithelial integrity. Dr. Muegge’s work has provided the first evidence that similar reprogramming may occur in the enteroendocrine lineage. He has used computational methods to identify candidate regulators of enteroendocrine cell secretion and will test those hypotheses using novel injury models in vitro and in vivo. He will identify mechanisms of EEC cellular and transcriptional adaptation to injury with single cell RNA sequencing. These efforts promise to fundamentally change our understanding of epithelial differentiation and identify new therapeutic targets to treat chronic injury. This K08 award will provide the necessary resources and skills that Dr. Muegge will require to become a successful independent investigator