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: 10475271
• 负责人: Joseph Scott Lee
• 金额: $ 14.74万
• 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/10475271
• 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; Persons; 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.

项目摘要 为了保护宿主并履行其共生作用，肠上皮细胞分泌大量 高度糖基化的粘蛋白至物理距离，但可以提供细菌栖息地和燃料，同时建立顶端 调节养分和废物通量的结合物。作为回报，健康的微生物群功能可提供 代谢物上皮依赖于功能。我们最近发表了嘌呤肾黄嘌呤（HPX）是 粘膜依赖于能量平衡，屏障功能和伤口的微生物群的代谢产物 愈合，建议HPX作为稳态粘膜代谢和功能的限制底物。公正 这项工作的扩展，我们证明了HPX诱导TP53诱导的糖酵解和凋亡调节剂 （Tigar）体外和体内表达并激活AMP激活的激酶（AMPK）。蒂加尔增加 通过磷酸五磷酸五磷酸途径的代谢物通量，而AMPK是代谢的主要调节剂 促进能量平衡。我们假设HPX从根本上通过Tigar塑造上皮代谢 AMPK作为支持肠内稳态和伤口愈合的机制。在这种情况下，嘌呤耗尽 并通过繁殖HPX生产的发达突变体的大肠杆菌通过殖民实验进行重构 被用来确定微生物群衍生的HPX对粘膜能量代谢的影响 功能和伤口愈合。 申请人李博士已经建立了一个科学的利基市场，以建立独立的基础 研究微生物核源性嘌呤在肠粘膜能量代谢和功能中的作用。李博士和 他的导师科尔根（Colgan 提供有关研究反馈，批评研究计划的奖项持续时间 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 促进李博士在基本肠道过程中知识基础的课程，以及 在结肠肠内收获/培养中建立的研究和组织病理学分析。李博士 将提交他的工作，以在他的研究的特定会议上展示，以与他的研究和网络分享 同事和潜在的合作者，并从科学界获得宝贵的反馈。李博士 不断参与粘膜炎症计划（MIP）的发展将受益， 纪律，多部门计划启动了研究粘膜炎症和解决方案的机制。 MIP培养了一个独特的实验室环境，用于医师科学家，临床医生和 研究科学家，并致力于建立一个供年轻研究人员蓬勃发展和发展的环境。这 为李博士构建的可用的设施和资源，提供了理想的环境， 他成功过渡到独立的道路。