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。项目摘要/摘要 衰老领域的一个基本问题是组织特异性成人茎的年龄相关的下降是否相关 细胞功能是可逆的。我们的初步研究专注于肠道，表明肠干细胞（ISC） 老鼠和人类减少了数字，从旧小鼠中隔离的肠道加密蛋 在ISC功能的体外器官测定中功能。我们还发现卡路里限制（CR）逆转了 衰老对ISC的影响。在哺乳动物肠中，大多数ISC Express LGR5都与 Paneth细胞，构成干细胞细胞邻居或“小裂”的组成部分。我们最近有 证明CR在幼鼠中通过降低雷帕霉素的机械靶标增强ISC功能 paneth细胞中的复合物1（mTORC1）信号传导，CR的这些作用可以被雷帕霉素模仿 （MTORC1抑制剂）。 Paneth细胞与ISC之间的这种相互作用是由Paneth中表达介导的 骨基质抗原1（BST-1）的细胞，一种产生旁分泌因子循环ADP结合起来的过胞酶 （CADPR）。通过该提案的三个目标在此过程中识别机械步骤 提高我们对CR如何保护生物体免受组织功能下降的理解。 具体而言，我们将测试CR和雷帕霉素增强ISC功能的假设诱导利基BST-1 在老鼠中（AIM 1）；转录因子PPAR-GAMMA在Paneth细胞中培养了这种反应（AIM 2）； CADPR激活的信号传导介导了ISC中的这一响应（AIM 3）。