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: 8900580
• 负责人: Omer Yilmaz
• 金额: $ 24.9万
• 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/8900580
• 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的年龄相关性下降是否 细胞功能是可逆的。针对肠道，我们的初步研究表明，肠道干细胞（ISC） 在老年小鼠和人类中数量减少，从老年小鼠中分离出的肠隐窝较少， 在ISC功能的体外类器官测定中具有功能。我们还发现，热量限制（CR）逆转了 老化对ISCs的影响。在哺乳动物肠道中，大多数ISCs表达Lgr 5，并且与Lgr 5相邻。 潘氏细胞，其构成干细胞细胞邻域或“小生境”的组成部分。我们最近 证明年轻小鼠的CR通过减少雷帕霉素的机制靶点来增强ISC功能 复合物1（mTORC 1）信号传导，并且CR的这些作用可以被雷帕霉素模拟 (an mTORC 1抑制剂）。潘氏细胞和ISCs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ADP核糖的胞外酶 （cADPR）。通过本提案的三个目标确定这一进程的机制步骤， 增加我们对CR如何保护生物体免受年龄相关的组织功能下降的理解。 具体地说，我们将检验CR和雷帕霉素诱导小生境Bst-1增强ISC功能的假设 转录因子PPAR-gamma介导潘氏细胞中的这种反应（Aim 2）; 并且cADPR激活的信号传导介导ISC中的这种应答（Aim 3）。