Intestinal homeostasis and aging

肠道稳态与衰老

• 批准号: 9030900
• 负责人: Heinrich Jasper
• 金额: $ 39.77万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030900
• 关键词: Address; Affect; Aging; Animals; Anterior; Automobile Driving; Barrett Esophagus; Biological Models; Cell Aging; Cell Differentiation process; Cell physiology; Cells; Characteristics; Chronic; Complex; Data; Development; Diet; Disease; Drosophila genus; Elderly; Enterocytes; Epithelium; Functional disorder; Gastric Metaplasia; Gastrointestinal tract structure; Gene Expression; Genetic; Goals; Health; Homeostasis; Human; IL6 gene; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Intervention; Intestinal Cancer; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Intestines; Intraepithelial Neoplasia; Lead; Life; Link; Longevity; Maintenance; Malignant Neoplasms; Mediating; Metaplasia; Metaplastic; Midgut; Modeling; Molecular; Natural regeneration; Organism; Pharmaceutical Preparations; Phenotype; Physiological; Population; Process; Regulation; Repression; Research; Role; Series; Signal Pathway; Signal Transduction; Stem cells; Stomach; Stress; System; Testing; Tissues; Vertebrates; age related; base; cell age; cell type; cytokine; disease phenotype; fly; functional loss; improved; innate immune function; insight; interest; intestinal epithelium; intestinal homeostasis; prevent; regenerative; spatiotemporal; tool; transcription factor

Summary The gastrointestinal tract is lined by a series of highly diverse epithelia that share important requirements (barrier function, innate immune function, secretory and absorptive functions), but also have distinct and highly specialized functions. Long-term maintenance of intestinal homeostasis depends on processes that maintain this morphological and functional diversity and reestablish it during regenerative episodes. Age-related loss of functional diversity can lead to metaplastic diseases, such as Barrett’s esophagus, that are associated with intestinal dysplasias and cancers. How aging affects compartment maintenance in the gut, and whether improving maintenance of compartment identities increases lifespan remains unclear. Here, the applicant presents preliminary data suggesting that age-related gastric metaplasia is caused by chronic inflammation and that it contributes to the loss of homeostasis of the aging gastrointestinal tract. Using Drosophila as a model system, the applicant finds that the JAK/Stat signaling pathway is chronically activated in differentiated cells of the aging gastric epithelium, and that this activation results in trans- differentiation of these cells into cell types characteristic of the posterior midgut epithelium. This metaplasia results in pH imbalance, commensal dysbiosis, and epithelial dysplasia, and shortens the lifespan of the animal. Accordingly, limiting JAK/Stat activity in the gastric region is sufficient to extend lifespan. Understanding the complex relationship of systemic inflammation, gastric metaplasia, and intestinal degeneration is expected to integrate various aspects of the pathophysiology of aging, providing new potential avenues for intervention. The applicant proposes the following specific aims: (i) establish the role of systemic and local inflammatory signals in the observed gastric metaplasia, (ii) characterize the mechanism of trans-differentiation of gastric cells into posterior midgut cells, (iii) assess the physiological consequences (including homeostasis of the intestinal epithelium and the commensal bacterial population, as well as lifespan) of compartment disruption in aging animals. Since the signaling mechanisms controlling regeneration in the gastrointestinal tract and the signals mediating systemic inflammatory responses are conserved between flies and vertebrates, it can be anticipated that the proposed study will provide important insight into the relationship between systemic inflammation and regenerative homeostasis in humans, and point to potential intervention strategies to improve homeostasis in the elderly and extend life- and healthspan.

概括 胃肠道由一系列高度潜水 要求（障碍功能，先天免疫功能，秘书和吸收功能），但 还具有独特的高度专业化功能。肠的长期维护 稳态取决于维持这种形态学和功能多样性的过程以及 在再生发作期间重新建立它。 与年龄相关的功能多样性丧失会导致跨性疾病，例如Barrett的疾病 食管，与肠道发育不全和癌症有关。衰老的影响 肠道中的隔室维护以及是否改善隔间维护 身份增加寿命尚不清楚。在这里，申请人介绍了初步数据 表明与年龄相关的胃化生症是由慢性炎症引起的 导致胃肠道衰老的体内稳态丧失。使用果蝇作为 模型系统，适用的发现JAK/Stat信号通路在长期激活 衰老胃上皮的分化细胞，这种激活导致反式 这些细胞将这些细胞分化为后中肠上皮的特征的细胞类型。这 化学导致pH失衡，共生营养不良和上皮发育不良，并缩短 动物的寿命。彼此之间，限制胃区域中的jak/stat活动就足够了 延长寿命。 了解全身注射，胃代PLASIA和 肠道变性有望整合衰老的病理生理的各个方面， 为干预提供新的潜在途径。申请人提出以下特定 目的：（i）在观察到的胃中确定系统性和局部炎症信号的作用 Metaplasia，（ii）表征了胃细胞转差的机理 中肠细胞，（iii）评估物理后果（包括肠内稳态 上皮和共生细菌种群以及隔室的寿命） 衰老动物的破坏。 由于控制胃肠道的再生的信号传导机制和 介导系统炎症反应的信号在苍蝇和脊椎动物之间保存， 可以预见的是，拟议的研究将为关系提供重要的见解 在人类的全身性炎症和再生稳态之间，并指出潜力 改善稳态的干预策略，并扩大寿命和健康状态。