Wnt Regulation of Tracheobronchial Regeneration

Wnt 调节气管支气管再生

基本信息

批准号：
7913504
负责人：
Susan D Reynolds
金额：
$ 34.08万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-11 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913504
关键词：
Ablation Acute Lung Injury Adult Respiratory Distress Syndrome Affect Basal Cell Basal Cell Hyperplasia Bronchopulmonary Dysplasia Bystander Effect Cell Communication Cell Differentiation process Cell Lineage Cell Maintenance Cells Characteristics Chronic Chronic lung disease Clinical Communication Complex Cues Cytokeratin Cytokeratin-14 Staining Method Data Derivation procedure Development Disease Disease Progression Dysplasia Elements Epithelial Epithelium Event Figs - dietary Functional disorder Gene Expression Gene Targeting Histopathology Homeostasis Human Hyperplasia Injury Knock-out Label Link Lung Lung diseases Maintenance Mediating Methods Mitotic Modeling Molecular Structure Mus Natural regeneration Nature Pathology Pathway interactions Phase Phenocopy Physiologic pulse Play Populations at Risk Process Recovery Regulation Research Design Role Secretory Cell Signal Pathway Signal Transduction Signal Transduction Pathway Source Staging Stem cells Symptoms System Testing Tissues Tracheobronchial Transgenes Transgenic Organisms Up-Regulation Variant airway remodeling base cell type cofactor cyclin D3 design end stage disease genetic manipulation genetic pedigree in vivo injury and repair insight intercellular communication precursor cell progenitor repaired research study response restoration stem cell fate specification treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Chronic airway diseases are characterized by alterations in the cellular composition of the tracheobronchial epithelium. Depletion of cells within the secretory/ciliated cell lineage and hyperplasia of cells within the basal cell lineage suggests that cell fate decisions at the level of a common precursor cell are dysregulated. The essential role played by the Wnt pathway in tracheobronchial development and reactivation of this pathway in regions of basal cell hyperplasia identify the Wnt signal transduction pathway as a potential regulator of tracheobronchial precursor cell differentiation. However, the complex pathology of end stage human lung disease prohibits identification of the source and target of Wnt signals. To this end, we have focused on developing genetically modified murine models that, in combination with quantitative histopathology, allow us to investigate the nature of precursor-progeny relationships in the epithelium and critical elements of Wnt signaling in the airway of intact mice. Previous studies have demonstrated that the tracheobronchial and bronchiolar regions are maintained by divergent stem cell hierarchies and suggest that the Wnt signal transduction pathway regulates distinct aspects of homeostasis and repair that may be critical to establishment and maintenance of structural and functional distinctions within these regions. Lineage tagging analysis has allowed us to conclude that the K14EC functions as the effecter cell in tracheobronchial regeneration and identification of multi-, uni-, and bi-potential K14EC-derived clones suggest that regulative processes influence differentiation of the K14EC. Preliminary studies identified p-catenin as a potential regulator of K14EC fate and the canonical Wnt signaling pathway as the proximal signaling mechanism leading to stabilization of p-catenin. These observations support the hypothesis that the tracheobronchial epithelium is maintained by a classical stem cell hierarchy and that cell fate decisions within this hierarchy are regulated by the canonical Wnt/p-catenin signal transduction pathway. Specific Aims will test this hypothesis in vivo through genetic manipulation of components of the canonical Wnt/p-catenin pathway and subsequent quantitative assessment of proliferation and differentiation. These studies are designed to identify mechanisms regulating the tracheobronchial stem cell hierarchy. Successful completion of this project will yield insights into critical transitions that are susceptible to dysregulation in human lung disease.

描述（由申请人提供）：慢性气道疾病的特征是气管上皮细胞的细胞组成改变。细胞内分泌/纤毛细胞谱系中细胞的耗竭和基础细胞谱系中细胞的增生表明，在共同前体细胞水平上的细胞命运决定失调。 Wnt途径在基底细胞增生区域中该途径的气管发育和重新激活中所起的基本作用确定Wnt信号转导途径是气管前体前体细胞分化的潜在调节剂。然而，终阶段人肺疾病的复杂病理禁止鉴定Wnt信号的来源和靶标。为此，我们专注于开发遗传修饰的鼠模型，这些模型与定量组织病理学结合使用，使我们能够研究上皮细胞中前体 - 实质关系的性质，以及在完整小鼠气道中Wnt信号的关键元素。先前的研究表明，气管支气管和支气管区域是通过不同的干细胞层次结构来维持的，并表明Wnt信号转导途径调节体内平衡的不同方面和修复可能对这些区域内结构和功能区别的建立和维持至关重要。谱系标记分析使我们得出结论，K14EC在气管支气管再生和鉴定多，单位和双电力K14EC衍生的克隆中的效应细胞表明，调节过程会影响K14EC的差异。初步研究将p-catenin确定为K14EC命运的潜在调节剂，而规范的Wnt信号通路是导致P-catenin稳定的近端信号传导机制。这些观察结果支持以下假设：气管支气管上皮由经典的干细胞层次结构维持，并且该层次结构中的细胞命运决策受规范的WNT/P-catenin信号转导途径调节。具体目的将通过对规范Wnt/p-catenin途径的组件的遗传操纵以及随后对增殖和分化的定量评估来检验这一假设。这些研究旨在确定调节气管干细胞层次结构的机制。该项目的成功完成将产生对容易受到人类肺部疾病失调的关键转变的见解。