Microbiota-sourced purines in gut health and disease

微生物群来源的嘌呤在肠道健康和疾病中的作用

• 批准号: 10283449
• 负责人: Joseph Scott Lee
• 金额: $ 14.89万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283449
• 关键词: 5' -AMP-activated protein kinase; Advisory Committees; Apical; Apoptosis; Apoptosis Regulation Gene; Award; Bacteria; Biogenesis; C57BL/6 Mouse; Caco-2 Cells; Cecum; Cells; Colitis; Collaborations; Colon; Communities; Complex; Critiques; Development; Development Plans; Differentiation Antigens; Disease; Energy Metabolism; Environment; Epithelial; Epithelial Cells; Escherichia coli; Feces; Feedback; Fostering; Foundations; Gastrointestinal tract structure; Genetically Modified Organisms; Germ-Free; Glycolysis; Growth; Gut Mucosa; Habitats; Harvest; Health; Histologic; Hypoxanthines; Immune system; Immunology; In Vitro; Inflammatory Bowel Diseases; Intervention; Intestinal Diseases; Intestines; Knock-out; Knockout Mice; Knowledge; Luciferases; Mediating; Mentors; Metabolic; Metabolism; Microbiology; Molds; Monitor; Mucins; Mucositis; Mucous Membrane; Mus; Mutation; Nucleotide Biosynthesis; Nucleotides; Nutrient; Oral; Oral Administration; Pathology; Pentosephosphate Pathway; Permeability; Physicians; Prevalence; Probiotics; Process; Production; Proliferating; Proliferation Marker; Publications; Publishing; Purines; Recovery; Research; Research Personnel; Resolution; Resources; Ribose; Role; SECTM1 gene; Scientist; Severity of illness; Small Interfering RNA; Source; Supplementation; TP53 gene; Testing; Therapeutic; Tissues; Treatment Efficacy; Undifferentiated; Work; career; cohort; dysbiosis; endoplasmic reticulum stress; energy balance; experimental study; gastrointestinal epithelium; gut health; host microbiota; in vivo; intestinal barrier; intestinal epithelium; intestinal homeostasis; knock-down; microbial; microbiota; microbiota metabolites; microorganism; multidisciplinary; mutant; next generation; programs; promoter; purine metabolism; reconstitution; response; symposium; transcription factor; wasting; wound healing

PROJECT SUMMARY To protect the host and perform their symbiotic role, intestinal epithelial cells secrete large amounts of highly glycosylated mucin to physically distance yet provide bacteria habitat and fuel, while establishing apical junction complexes that regulate nutrient and waste flux. In return, a healthy microbiota functions to provide metabolites the epithelium relies on for function. We recently published that the purine hypoxanthine (Hpx) is a microbiota-derived metabolite that the mucosa depends upon for energy balance, barrier function, and wound healing, suggesting Hpx as a limiting substrate for homeostatic mucosal metabolism and function. In unbiased extensions of that work, we demonstrated that Hpx induces TP53-inducible glycolysis and apoptosis regulator (TIGAR) expression and activates AMP-activated kinase (AMPK) in vitro and in vivo. TIGAR increases metabolite flux through the pentose phosphate pathway while AMPK is a master regulator of metabolism that promotes energy balance. We hypothesize that Hpx fundamentally molds epithelial metabolism through TIGAR and AMPK as mechanisms that support intestinal homeostasis and wound healing. In this, purine depletion and reconstitution by colonization experiments with a developed mutant E. coli enriched in Hpx production will be employed to determine the influence of microbiota-derived Hpx on mucosal energy metabolism, barrier function, and wound healing. The applicant, Dr. Lee, has established a scientific niche in which to build a foundation for independent research in the role of microbiota-derived purines in gut mucosal energy metabolism and function. Dr. Lee and his mentor, Dr. Colgan, assembled an advisory committee to regularly meet as a group with Dr. Lee throughout the duration of the award to provide feedback on the research, critique the research plans, monitor publications, and provide career advice. Drs. Colgan and Lee also identified microbiology and immunology courses to facilitate expansion of Dr. Lee's foundation of knowledge in fundamental intestinal processes, and established tutelage in colonic enteroid harvesting/culturing for study and in histopathological analyses. Dr. Lee will submit his work to present at conferences specific to his research to share his research and network with colleagues and potential collaborators, and get valuable feedback from the scientific community. Dr. Lee's development will benefit from continued participation in the Mucosal Inflammation Program (MIP), a multi- disciplinary, multi-departmental program initiated to study mechanisms of mucosal inflammation and resolution. The MIP fosters a unique lab environment for collaboration between physician scientists, clinicians, and research scientists, and works to establish an environment for young investigators to flourish and develop. The facilities and resources available to and development plan built for Dr. Lee provide an ideal environment and path for his successful transition to independence.

项目概要 为了保护宿主并发挥其共生作用，肠上皮细胞分泌大量的 高度糖基化的粘蛋白以物理距离提供细菌栖息地和燃料，同时建立顶端 调节营养物和废物通量的连接复合体。作为回报，健康的微生物群可以提供 上皮发挥功能所依赖的代谢物。我们最近发表了嘌呤次黄嘌呤 (Hpx) 是一种 粘膜赖以维持能量平衡、屏障功能和伤口的微生物群衍生代谢物 愈合，表明 Hpx 作为稳态粘膜代谢和功能的限制底物。在不偏不倚的情况下 该工作的扩展，我们证明 HPx 诱导 TP53 诱导的糖酵解和细胞凋亡调节剂 (TIGAR) 表达并在体外和体内激活 AMP 激活激酶 (AMPK)。 TIGAR 增加 通过戊糖磷酸途径的代谢物通量，而 AMPK 是代谢的主要调节因子 促进能量平衡。我们假设 Hpx 通过 TIGAR 从根本上塑造上皮代谢 AMPK 作为支持肠道稳态和伤口愈合的机制。在这种情况下，嘌呤消耗 并通过用富含 HPx 生产的已开发突变体大肠杆菌进行定植实验进行重建将 用于确定微生物群衍生的 HPx 对粘膜能量代谢、屏障的影响 功能和伤口愈合。 申请人李博士已经建立了一个科学领域，为独立的研究奠定了基础。 研究微生物群衍生的嘌呤在肠道粘膜能量代谢和功能中的作用。李博士和 他的导师科尔根博士组建了一个咨询委员会，在整个过程中定期与李博士会面。 奖励期限提供研究反馈、批评研究计划、监督 出版物，并提供职业建议。博士。科尔根和李还确定了微生物学和免疫学 课程，以促进李博士在基本肠道过程方面知识基础的扩展，以及 建立了结肠肠样采集/培养研究和组织病理学分析的指导。李博士 将提交他的作品并在特定于他的研究的会议上展示，以与他人分享他的研究和网络 同事和潜在的合作者，并从科学界获得宝贵的反馈。李博士的 持续参与粘膜炎症计划 (MIP) 将受益于该计划的发展，该计划是一项多方 启动了多学科的学科计划，以研究粘膜炎症和消退的机制。 MIP 为医师科学家、临床医生和医生之间的合作营造了一个独特的实验室环境。 研究科学家，并致力于为年轻研究人员创造一个蓬勃发展的环境。这 为李博士提供的设施和资源以及为他制定的发展计划提供了理想的环境和 他成功过渡到独立的道路。