Regulation of Active and Quiescent Intestinal Stem Cells

活性和静态肠干细胞的调节

• 批准号: 8534780
• 负责人: Kelley Yan
• 金额: $ 14.34万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534780
• 关键词: Achievement; Cell Count; Cell Hypoxia; Cell Lineage; Cells; Culture Techniques; Data; Dose; Employee Strikes; Epithelial; Epithelium; Exhibits; G-Protein-Coupled Receptors; Gene Expression Profiling; Genes; Genetic; Hair follicle structure; Homeostasis; Hypoxia; Hypoxia Inducible Factor; In Vitro; Injury; Intestinal Diseases; Intestines; Lead; Life; Maintenance; Manuscripts; Metabolic; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; Natural regeneration; Organ Size; Oxygen; Pathway interactions; Physiological; Polycomb; Population; Positioning Attribute; Proliferating; Proteins; Radiation Injuries; Regulation; Reporter; Resistance; Signal Pathway; Signal Transduction; Small Intestines; Stem cells; Tissue Model; Tissues; Validation; Villus; adult stem cell; base; bone; candidate validation; comparative; extracellular; gain of function; improved; in vivo; insight; intestinal crypt; intestinal epithelium; irradiation; loss of function; molecular marker; novel strategies; regenerative; repaired; response; self-renewal; stem cell biology; stem cell niche; stem cell population; tissue regeneration; transcriptome sequencing

DESCRIPTION (provided by applicant): There is emerging evidence that distinct populations of actively cycling and quiescent intestinal stem cells (ISCs) co-exist within the small intestine epithelium and function cooperatively in tissue renewal. This proposal explores the hypothesis that these ISC populations are regulated by distinct sets of extracellular signals involved in organ size control and oxygen-sensing. This hypothesis is evaluated by three Specific Aims: (1) to explore the Hippo signaling pathway, implicated in controlling organ size, in regulating the regenerative responses of active and quiescent ISC populations, (2) to examine metabolic regulation of active and quiescent ISCs by the oxygen-sensing pathway, and (3) to determine the molecular signatures of active versus quiescent ISCs by comparative gene expression profiling. These Specific Aims will be achieved by employing rigorous mouse genetics to examine ISCs in vivo within their stem cell niches and validated ex vivo clonogenic culture techniques that allow for sustained proliferation and multi-lineage differentiation of single isolated ISCs. Achievement of these Aims should provide insight into the molecular differences between active and quiescent ISCs at the transcriptional level and their differential regulation by diverse pathways governing organ size and metabolism.

描述（由申请人提供）：有新的证据表明，活跃循环和静止的肠干细胞（ISCs）的不同群体共存于小肠上皮内，并在组织更新中协同发挥作用。该提案探讨了这一假设，即这些ISC群体是由参与器官大小控制和氧传感的不同细胞外信号集调节的。该假设通过三个特定目的进行评估：（1）探索Hippo信号通路，其涉及控制器官大小、调节活性和静止ISC群体的再生反应，（2）通过氧传感通路检查活性和静止ISC的代谢调节，以及（3）通过比较基因表达谱确定活性与静止ISC的分子特征。这些特定目的将通过采用严格的小鼠遗传学在其干细胞小生境内体内检查ISC以及允许单个分离的ISC持续增殖和多谱系分化的经验证的离体克隆形成培养技术来实现。这些目标的实现将提供对活性和静止ISCs在转录水平上的分子差异的深入了解，以及它们通过以下途径的差异调节： 控制器官大小和新陈代谢的不同途径。