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: 8094196
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094196
• 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; Wound Healing; 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

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.

概述：本提案的目标是确定调节气管支气管上皮组织特异性干细胞（TSC）及其生态位之间相互作用的细胞和分子机制。TSC自我更新和分化程序的失调已被认为是许多上呼吸道疾病，如COPD，哮喘和CF。