A Promitotic Stem Cell Niche: Role For Beta-Catenin and TGFbeta

促有丝分裂干细胞生态位：β-连环蛋白和 TGFbeta 的作用

• 批准号: 8274642
• 负责人: Moumita Ghosh
• 金额: $ 12.22万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-06 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274642
• 关键词: Address; Adult; Applications Grants; Asthma; Basal Cell; Biological Assay; Biological Models; Bromodeoxyuridine; Cell Count; Cell Nucleus; Cell Proliferation; Cell Therapy; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Clone Cells; Cues; Data; Development; Disease; Duct (organ) structure; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Gene Expression; Generations; Genetic; Gland; Goals; Growth Factor; Home environment; Human; In Vitro; Individual; Injury; Keratin; Knowledge; Label; Left; Maintenance; Methods; Mitotic; Modification; Molecular; Mus; Naphthalene; Nature; Organ; Outcome; Pathway interactions; Phenotype; Play; Property; Refractory; Role; Seeds; Serial Passage; Signal Pathway; Signal Transduction; Soil; Stem cells; Structure of parenchyma of lung; Surface; Testing; Text; Therapeutic Intervention; Time; Tissues; Trachea; Tracheobronchial; Transforming Growth Factor beta; Transgenic Model; Undifferentiated; base; beta catenin; cell behavior; cell type; cohort; density; in vitro testing; injured; innovation; programs; public health relevance; receptor; repaired; self renewing cell; self-renewal; stem; stem cell niche; tissue repair

DESCRIPTION (provided by applicant): Overview: The goal of this proposal is to identify the cellular and molecular mechanisms that regulate interactions between the tracheobronchial epithelial tissue-specific stem cell (TSC) and its niche. Dysregulation of the TSC self-renewal and differentiation program has been suggested for many upper airway diseases like COPD, asthma, and CF. My preliminary data indicate that mouse tracheal TSCs generate their own niche that is promitotic in nature and modification of this niche is necessary for differentiation. This modification is accomplished by environmental cues derived from differentiated tracheal cells. Based on this preliminary data, I will determine 1) the role of these TSCs in tissue repair, and 2) the signaling pathways involved in maintenance of the proliferative niche. Significance of the study: This study will advance the field of lung TSC by addressing 2 fundamental paradigms: 1) TSC participation in repair of the damaged epithelium, and 2) signaling pathways that allow differentiation of transit amplifying cells (TAC). Finally, this study provides an important modification of the "seed and soil" paradigm for cell-based therapy by raising the possibility that introduction of pure stem/niche cells to an injured organ may result in unrestrained expansion of the mitotic cohort due to disease-associated depletion of the differentiated cells that modify the niche. Innovation: Development of a rim-clone assay allows generation of large number of TAC (8x10^3) from a single TSC. This method will permit analysis of signaling mechanisms using TSC from genetically-modified mice, through cell-mixing studies and using pharmacological approaches. Thus, I will have the ability to evaluate TSC proliferation and differentiation under controlled conditions for the first time.

描述（由申请人提供）：概述：该提案的目的是确定调节气管上皮组织特异性干细胞（TSC）与其利基市场之间相互作用的细胞和分子机制。对于COPD，哮喘和CF，TSC自我更新和分化计划的失调。 我的初步数据表明，小鼠气管TSC会产生自己的利基市场，而这种利基在本质上是有希望的，并且对这种利基的修改是分化所必需的。这种修饰是通过从分化的气管细胞中得出的环境提示来完成的。基于此初步数据，我将确定1）这些TSC在组织修复中的作用，以及2）涉及维持增殖生态位的信号传导途径。 研究的意义：本研究将通过解决2种基本范例来推进肺TSC的领域：1）TSC参与受损上皮的修复，以及2）允许分化运输扩增细胞（TAC）的信号传导途径。最后，这项研究通过提高将纯茎/小裂细胞引入受伤器官的可能性可能导致因疾病相关细胞的耗尽而导致脱粒细胞的耗尽而导致脱粒细胞的耗尽，从而对基于细胞的治疗的“种子和土壤”范式进行了重要修改。 创新：RIM-CLONE测定的开发允许从单个TSC生成大量的TAC（8x10^3）。该方法将允许使用来自遗传改性小鼠的TSC，通过细胞混合研究和使用药理学方法来分析信号传导机制。因此，我将首次评估在受控条件下的TSC增殖和分化的能力。