Intestinal Stem Cell Culture and Entero-Endocrine Lineage Development

肠道干细胞培养和肠内分泌谱系发育

• 批准号: 9529874
• 负责人: James C Dunn
• 金额: $ 8.88万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9529874
• 关键词: Address; Adult; Affect; Animal Model; Applications Grants; Autologous; Biological Models; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cell division; Cells; Characteristics; Child; Clinic; Daughter; Defect; Development; Dinoprostone; Disease; Engraftment; Epithelial; Epithelium; Equilibrium; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Goals; Growth; Homeostasis; Human; Human Characteristics; In Situ; In Vitro; Injury; Integrins; Intestines; Laboratories; Laminin; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Myofibroblast; Natural regeneration; Oxygen; Pattern; Phase; Pluripotent Stem Cells; Process; Regenerative Medicine; Research; Role; Sampling; Secretory Cell; Signal Transduction; Small Intestines; Stem cells; Stress; Structure; TACSTD1 gene; Translating; Transplantation; cell growth; experience; extracellular; implantation; improved; in vitro Model; in vivo; induced pluripotent stem cell; insight; intestinal epithelium; member; mouse model; novel; public health relevance; self-renewal; smoothened signaling pathway; stem cell biology; stem cell niche; stem cell population; stemness; tool

DESCRIPTION (provided by applicant): The molecular basis of intestinal stem cell biology in both humans and mice is a subject of active research. The goal of this application is to identify the mediators that influence the interaction of human intestinal stem cells with intestinal myofibroblasts in order to enhance the regeneration of human small bowel epithelium. This is a necessary step toward the development of novel cellular therapies for disorders associated with intestinal failure in children. To bring such therapies to the clinic, it will be essential to recapitulate the in situ characteristics of the intestinal epithelium. We will focus on assessing te mechanism by which human intestinal stem cells undergo self-renewal and differentiation. Specifically, we will assess the role of R-Spondin and WNT5a in maintaining stemness of these cells. We will also assess the mechanism by which Hedgehog signaling and the stress induced by alterations of oxygen tension and pH modulate the interaction between intestinal stem cells and myofibroblasts. Lastly, we will assess whether specific laminin and integrin isotypes alter intestinal stem cell growth and differentiation, and whether they affect cellular engraftment in recipient animal models. At the completion of this study, we anticipate that we will be able to define the mediators that control these stem cell characteristics, which will lead to novel cellula therapies.

描述（由申请人提供）：人类和小鼠肠道干细胞生物学的分子基础是一个活跃的研究主题。该应用的目标是确定影响人肠道干细胞与肠道肌成纤维细胞相互作用的介质，以增强人小肠上皮的再生。这是开发针对儿童肠衰竭相关疾病的新型细胞疗法的必要步骤。为了将这种疗法引入临床，必须概括肠上皮的原位特征。我们将重点评估人类肠道干细胞自我更新和分化的机制。具体来说，我们将评估 R-Spondin 和 WNT5a 在维持这些细胞干性中的作用。我们还将评估 Hedgehog 信号传导以及氧张力和 pH 值变化引起的应激调节肠道干细胞和肌成纤维细胞之间相互作用的机制。最后，我们将评估特定的层粘连蛋白和整合素同种型是否会改变肠道干细胞的生长和分化，以及它们是否会影响受体动物模型中的细胞植入。在这项研究完成后，我们预计我们将能够定义控制这些干细胞特征的介质，这将导致新的细胞疗法。