Regulation of intestinal stem cell behavior by occluding junctions

通过封闭连接来调节肠道干细胞行为

• 批准号: 9319074
• 负责人: DANA LEANNE JONES
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319074
• 关键词: Acute; Adult; Age; Aging; Animals; Apical; Arthropods; Biological Assay; Blood; Cell Differentiation process; Cell Proliferation; Cells; Chronic; Colon Carcinoma; Complex; Crohn' s disease; Data; Daughter; Defect; Degenerative Disorder; Development; Disease; Drosophila genus; Drosophila melanogaster; Embryo; Employee Strikes; Enterocytes; Enteroendocrine Cell; Epidermal Growth Factor Receptor; Epithelial; Event; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genes; Hindgut; Homeostasis; Human; Immunity; Individual; Inflammation; Intercellular Junctions; Intestinal Diseases; Intestines; Life; Liver; Longevity; Maintenance; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediating; Metabolic; Midgut; Modeling; Molecular; Muscle; Natural regeneration; Nutrient; Pathway interactions; Permeability; Phenotype; Play; Proteins; RNA Interference; Regulation; Role; Septate; Signal Transduction; Skin; Stem Cell Factor; Stem cells; Structure; Surface; Testing; Tight Junctions; Time; Tissues; Toxic Environmental Substances; Ulcerative Colitis; Vertebrates; Water; Work; age related; aged; analog; cell age; cell behavior; fly; gliotactin; innate immune function; interstitial; intestinal epithelium; intestinal homeostasis; loss of function; macromolecule; microbial; neuroglian; novel; organ regeneration; prevent; stem cell niche; tissue regeneration; uptake

Project Summary Maintenance and regeneration of tissues such as skin, liver, blood, and muscle decrease dramatically with age; however, molecular mechanisms that could serve to coordinate tissue and organismal aging have not been elucidated. Furthermore, it is not known whether the function of one tissue is more important than others in influencing healthspan and longevity. Aging results in loss of intestinal barrier function in species ranging from flies to humans; however, the increase in vulnerability to intestinal dysfunction in older individuals is not fully understood. Here we propose to develop the Drosophila melanogaster digestive tract as a model to study the relationship between the complexes that constitute the intestinal barrier and intestinal stem cell (ISC) behavior, as well as mechanisms underlying the age-related loss of intestinal barrier function. The intestinal epithelium provides a selective barrier that permits nutrient and water transport, while preventing uptake of harmful environmental toxins and microbial contamination of interstitial tissues. In addition to its barrier function, the intestinal epithelium also serves essential metabolic and innate immune functions. In mammals, loss of intestinal barrier function and increased intestinal permeability correlates with compromised integrity of cell-cell junctions, known as tight junctions (TJs). Septate junctions (SJs), the Drosophila analog of vertebrate TJs, are important for regulating paracellular flow between apical and basal epithelial surfaces. The SJ components in the Drosophila intestine have not been fully characterized, and their potential role in maintaining intestinal integrity throughout aging has not been interrogated. Our preliminary data indicate that there are age-related changes in the expression and localization of SJ components in the Drosophila posterior midgut. For example, we find alterations at tricellular junctions (TCJ), specialized structures where three/four cells converge, as well as cytoplasmic accumulation of several SJ components. Therefore, we hypothesize that loss of SJ/TCJ function with age leads to rapid changes in ISC behavior, which contribute to loss of intestinal homeostasis in older animals. We will test this directly through the following Specific Aims: 1) To characterize the role of TCJ in regulating ISC behavior and intestinal aging phenotypes 2) To assess the role of bicellular SJ in regulating ISC behavior and intestinal aging phenotypes 3) To explore the role of Neuroglian (Nrg) in the Drosophila intestine The causal relationships between increased ISC proliferation, loss of intestinal integrity, metabolic defects, increased inflammation, and dysbiosis are not known. Here we propose to investigate age-related changes in occulding junctions as a proximal event, leading to changes in ISC behavior and, ultimately, loss of tissue homeostasis. Our findings will have major implications for the treatment of gasterointestinal diseases and disorders, chronic inflammation, and cancer, particularly in older individuals.

项目摘要 皮肤、肝脏、血液和肌肉等组织的维持和再生显著减少 年龄；然而，能够协调组织和组织衰老的分子机制还没有 已被阐明。此外，还不知道一个组织的功能是否比其他组织的功能更重要 在影响健康和长寿方面。老化导致物种饲养中肠道屏障功能的丧失 从苍蝇到人类；然而，老年人对肠道功能障碍的易感性增加并不是 完全理解。在这里，我们建议发展果蝇的消化道作为研究的模型 构成肠道屏障的复合体与肠道干细胞的关系 (ISC)行为，以及与年龄相关的肠道屏障功能丧失的潜在机制。 肠道上皮提供了一种选择性屏障，允许营养和水的运输，而 防止有害环境毒素的吸收和间质组织的微生物污染。在……里面 除了屏障功能，肠上皮还提供必要的新陈代谢和先天免疫。 功能。在哺乳动物中，肠道屏障功能的丧失和肠道通透性的增加与 细胞-细胞连接的完整性受损，称为紧密连接(TJ)。分隔结点(SJS)、 果蝇类似于脊椎动物的TJ，对调节顶端和基底端之间的细胞旁血流很重要 上皮面。果蝇肠道中的SJ组分还没有完全确定，它们的 在整个衰老过程中保持肠道完整性的潜在作用尚未被询问。我们的预赛 数据表明，SJ组分的表达和定位存在年龄相关性变化 果蝇的后中肠。例如，我们发现三细胞连接(Tcj)的变化， 3/4细胞汇聚的特化结构，以及几个SJ的细胞质聚集 组件。因此，我们假设随着年龄的增长，Sj/Tcj功能的丧失会导致ISC的快速变化 行为，这是造成老年动物肠道内环境平衡丧失的原因。我们将直接通过 以下是具体目标： 1)研究tcj在调节isc行为和肠道衰老表型中的作用。 2)评价双细胞SJ在调节ISC行为和肠道衰老表型中的作用 3)探讨神经胶质细胞在果蝇肠道中的作用 ISC增殖增加、肠道完整性丧失、代谢缺陷、 炎症增加和生物失调尚不清楚。在这里，我们建议研究与年龄相关的变化 在作为近端事件的掩蔽连接中，导致ISC行为的改变，并最终失去 组织动态平衡。我们的发现将对胃肠道疾病的治疗具有重要意义。 疾病、慢性炎症和癌症，特别是在老年人中。