Regulation of the Intestinal Stem Cell Niche in Aging

衰老过程中肠道干细胞生态位的调节

• 批准号: 8919197
• 负责人: Omer Yilmaz
• 金额: $ 24.15万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919197
• 关键词: Address; Adult; Age; Aging; Agonist; Antigens; Biological Assay; Calcium; Calcium Signaling; Caloric Restriction; Cell Count; Cell physiology; Cells; Chromatin; Complex; Cyclic ADP-Ribose; Data; Doxycycline; Engineering; Enzymes; Flow Cytometry; Functional disorder; Gene Expression Profiling; Genetic Transcription; Human; In Vitro; Injury; Intervention; Intestines; Longevity; Mediating; Microscopy; Molecular; Mus; Natural regeneration; Neighborhoods; Organ; Organism; Organoids; PPAR gamma; Paneth Cells; Peroxisome Proliferator-Activated Receptors; Process; Protein Isoforms; Regulation; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Signal Transduction; Sirolimus; Stem cells; Testing; Tissues; Transgenic Mice; abstracting; adult stem cell; age effect; age related; bone; extracellular; feeding; in vivo; inhibitor/antagonist; intestinal crypt; paracrine; prevent; receptor; repaired; research study; response; stem cell niche; transcription factor

7. Project Summary/Abstract A fundamental question in the aging field is whether the age-related decline in tissue-specific adult stem cell function is reversible. Focused on the gut, our preliminary studies suggest that intestinal stem cell (ISC) numbers are reduced in old mice and humans and that intestinal crypts isolated from old mice are less functional in an in vitro organoid assay of ISC function. We also find that calorie restriction (CR) reverses the effects of aging on ISCs. In the mammalian intestine, a majority of ISCs express Lgr5 and are adjacent to Paneth cells, which constitute a component of the stem cell cellular neighborhood or “niche”. We have recently demonstrated that CR in young mice augments ISC function by reducing mechanistic target of rapamycin complex 1 (mTORC1) signaling in Paneth cells, and that these effects of CR can be mimicked by rapamycin (an mTORC1 inhibitor). This interaction between Paneth cells and ISCs is mediated by expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR). Identification of the mechanistic steps in this process through the three aims of this proposal will increase our understanding of how CR protects an organism against the age-related decline in tissue function. Specifically, we will test the hypotheses that induction of niche Bst-1 by CR and rapamycin boosts ISC function in old mice (Aim 1); that the transcription factor PPAR-gamma mediates this response in Paneth cells (Aim 2); and that cADPR-activated signaling mediates this response in ISCs (Aim 3).

7. 项目总结/摘要 衰老领域的一个基本问题是组织特异性成体干细胞是否与年龄相关的下降 细胞功能是可逆的。我们的初步研究重点关注肠道，表明肠道干细胞 (ISC) 年老小鼠和人类的数量减少，并且从年老小鼠中分离出的肠隐窝也较少 在 ISC 功能的体外类器官测定中发挥作用。我们还发现热量限制（CR）可以逆转 衰老对 ISC 的影响。在哺乳动物肠道中，大多数 ISC 表达 Lgr5 并且邻近 潘氏细胞，构成干细胞细胞邻域或“生态位”的组成部分。我们最近有 证明年轻小鼠的 CR 通过减少雷帕霉素的机械靶标来增强 ISC 功能 潘氏细胞中的复合物 1 (mTORC1) 信号转导，并且 CR 的这些作用可以通过雷帕霉素来模拟 （一种 mTORC1 抑制剂）。潘氏细胞和 ISC 之间的这种相互作用是由潘氏细胞中的表达介导的 骨基质抗原 1 (Bst-1) 细胞，一种产生旁分泌因子环状 ADP 核糖的胞外酶 (cADPR)。通过本提案的三个目标确定该过程中的机械步骤将 增加我们对 CR 如何保护生物体免受与年龄相关的组织功能衰退的理解。 具体来说，我们将测试 CR 和雷帕霉素诱导小生境 Bst-1 增强 ISC 功能的假设 在老年小鼠中（目标 1）；转录因子 PPAR-gamma 在潘氏细胞中介导这种反应（目标 2）； cADPR 激活的信号传导在 ISC 中介导这种反应（目标 3）。