Enteroendocrine cell plasticity during intestinal injury

肠道损伤期间肠内分泌细胞的可塑性

• 批准号: 9806688
• 负责人: Brian David Muegge
• 金额: $ 12.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806688
• 关键词: Address; Advisory Committees; Animals; Award; Basic Science; Biological Models; Biology; Cell Line; Cell Nucleus; Cell physiology; Cell secretion; Cells; Chronic; Clinical; Clinical Endocrinology; Coculture Techniques; Computing Methodologies; Cytokine Receptors; Data Set; Development; Developmental Biology; Digestion; Doctor of Medicine; Doctor of Philosophy; Endocrine; Endocrinology; Enteroendocrine Cell; Epithelial; Faculty; Future; Genetic Transcription; Goals; Goblet Cells; Growth Factor; Health; Healthcare Systems; Heterogeneity; Hormone secretion; Hormones; Human; Immunotherapy; Impairment; In Vitro; Infection; Inflammation; Inflammatory Bowel Diseases; Injury; Interleukin 6 Receptor; Internal Medicine; International; Intestinal Diseases; Intestines; K-Series Research Career Programs; Mentors; Mentorship; Meta-Analysis; Metabolic Diseases; Methods; Modeling; Nuclear RNA; Paneth Cells; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Population; Punch Biopsy; Receptor Signaling; Regulation; Reporting; Research; Research Personnel; Resources; Role; Satiation; Scientist; Signal Transduction; Somatotropin; Source; Starvation; Stem cells; System; Systems Biology; Testing; Therapeutic; Training; Travel; Universities; Villus; Vocational Guidance; Washington; Work; Wound Healing; analytical method; career; cytokine; gut microbiome; healing; improved; in vitro Model; in vivo; injured; insight; insulin secretion; intestinal homeostasis; monolayer; mouse model; new therapeutic target; novel; recruit; repaired; response; response to injury; single cell sequencing; single-cell RNA sequencing; skills; small molecule; stem; transcriptome sequencing; wound

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

项目总结/摘要 该提案的目标是制定一个5年计划，以准备Brian Muegge，M.D.，哲学博士、成为 研究肠道内分泌细胞在肠道损伤中的作用的独立医生科学家。他 获得了医学博士学位和博士他在华盛顿大学获得学位，在那里他研究肠道微生物组。 经过内科和内分泌学的临床培训后，Muegge博士加入了Thaddeus博士的实验室。 斯塔彭贝克在那里，他发现肠内分泌细胞在损伤过程中发生了动态变化 以增加促进肠道愈合的因子的表达。罕见的肠内分泌 细胞在损伤过程中经历适应性重编程建立了一个重要的新范式， 生物学他通过开发新的体外模型系统来扩展这些发现， 肠内分泌细胞，沿着实验和分析方法分离和转录谱 这些细胞的单个细胞核。这项工作是提案中各项目标的基础。 该项目的中心指导将由导师Stappenbeck博士提供。Stappenbeck博士a 他是国际公认的肠干细胞和伤口修复专家。他有一 在为独立职业做准备时，培训医生-科学家的杰出记录。另外。 博士Muegge组建了一个由内分泌学、发育学和免疫学专业人员组成的咨询委员会。 生物学和单核RNA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 随时可用。 这项提案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 它们响应损伤信号的活性（分泌）或分化状态。斯坦彭贝克博士的实验室 先前描述了肠道的吸收细胞如何使用改变的适应性重编程来实现 恢复上皮完整性的新表型。Muegge博士的工作首次提供了类似证据 重编程可发生在肠内分泌谱系中。他用计算方法 肠内分泌细胞分泌的候选调节因子，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。 分化和识别新的治疗靶点以治疗慢性损伤。K 08奖项将提供 Muegge博士成为一名成功的独立研究者所需的必要资源和技能