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: 8560030
• 负责人: Omer Yilmaz
• 金额: $ 13.74万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8560030
• 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; adult stem cell; age effect; age related; bone; extracellular; feeding; in vivo; inhibitor/antagonist; intestinal crypt; paracrine; prevent; public health relevance; receptor; repaired; research study; response; stem cell niche; transcription factor

DESCRIPTION (provided by applicant): 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 wil 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).

描述（由申请人提供）：衰老领域中的一个基本问题是组织特异性干细胞功能的年龄相关的下降是否可逆。我们的初步研究专注于肠道，这表明肠道干细胞（ISC）的数量减少了老鼠和人类，并且从旧小鼠中分离出的肠道隐窝在ISC功能的体外器官测定中的功能较小。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表达LGR5，并且与Paneth细胞相邻，该细胞构成了干细胞细胞邻居或“小裂”的组成部分。我们最近证明，在幼体中，CR通过减少帕氏蛋白酶复合物1（MTORC1）信号的机理靶标在Paneth细胞中增强ISC功能，并且CR的这些作用可以被雷帕霉素（MTORC1抑制剂）模仿。 Paneth细胞与ISC之间的这种相互作用是由骨基质抗原1（BST-1）的平底细胞中的表达介导的，这是一种产生旁分泌因子循环ADP Ribose（CADPR）的骨酶。通过该提案的三个目标来识别此过程中的机械步骤，将增加我们对CR如何保护有机体免受组织功能下降的理解。具体而言，我们将测试CR和雷帕霉素在旧小鼠中提高ISC功能诱导nike BST-1的假设（AIM 1）；转录因子PPAR-GAMMA介导了Paneth细胞中的这种反应（AIM 2）； CADPR激活的信号传导介导了ISC中的这一响应（AIM 3）。