An Integrated Approach to Airway Epithelial Repair and Regeneration

气道上皮修复和再生的综合方法

基本信息

批准号：
8403689
负责人：
BRIGID L.M. HOGAN
金额：
$ 64.64万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403689
关键词：
Address Adhesions Adult Air Architecture Basal Cell Biological Assay Biological Models Cell Proliferation Cell Separation Cells Cessation of life Chronic Commit Cultured Cells Data Data Set Databases Defect Development Developmental Cell Biology Disease Distal Engineering Engraftment Epidermis Epithelial Epithelial Cells Epithelium Exogenous Factors Family Family member Fibrosis Gene Expression Profile Gene Targeting Generations Genes Homeostasis Human In Vitro Inflammation Injury Instruction Liquid substance Lung Lung diseases Messenger RNA MicroRNAs Modeling Molecular Mus National Heart, Lung, and Blood Institute Natural regeneration Organoids Pathologic Pathology Pathway interactions Phenotype Physiological Pluripotent Stem Cells Principal Investigator Proliferating Proteins Pseudostratified Epithelium RNA Sequences Rana Regulation Research Resources Role Site Stem cells Structure of parenchyma of lung Techniques Technology Testing Therapeutic Tissues Transplantation Wound Healing Xenopus airway epithelium airway obstruction base cell behavior cost effective design gene repair in vivo injured airway innovation insight interest knowledge base lung repair member next generation next generation sequencing novel novel marker novel therapeutics prevent progenitor reconstruction repaired research study response self-renewal skills stem stem cell biology stem cell niche tool transcription factor

项目摘要

According to the NHLBI, airway diseases are the leading cause of U.S. deaths due to lung disease. Defects in epithelial homeostasis and repair underlie pathologic remodeling seen in many lung disorders and contribute to chronic inflammation, fibrosis and airway obstruction. The overarching rationale of this proposal is that novel therapeutic strategies to prevent or reverse airway pathology and to engineer lung tissue from pluripotent stem cells will be greatly enhanced by a more thorough understanding of endogenous human regional epithelial stem cells, how they self renew, produce committed progenitors and differentiate to create a functional polarized epithelium. The team combines expertise in cell and developmental biology, stem cell biology and human lung pathobiology and exploits frog, mouse and human models in three highly interrelated aims. Aim 1 builds on a comprehensive next generation sequencing database of dynamic changes in mRNAs and microRNAs (miRs) in human bronchial epithelial cells undergoing differentiation in vitro. It tests the hypothesis that specific mlRs regulate progenitor cell proliferation and cell fate decisions in vivo during generation and repair of a mucociliary epithelium. Aim 2 Is based on studies in mice characterizing epithelial progenitor cells in large and small ainways. It combines novel cell sorting strategies for cell isolation with 3D culture and transplantation techniques to characterize poorly understood, but critically important, human small ainway progenitors. Next generation RNA sequencing will then be used to generate a comprehensive database of mRNA and miRs in these cells. Aim 3 is based on studies showing dynamic regulation of grainyhead like transcription factors in an in vivo airway injury model and seeks to understand their role to integrate and coordinate epithelial polarity and barrier function during repair and regeneration. As well as bringing unique assays, model systems, technologies and resources to the Consortium, the proposed experiments will provide novel data about lung stem and progenitor cells that will help guide therapeutic strategies to mitigate or prevent ainway pathology and to enhance lung repair, regeneration and reconstruction. RELEVANCE (See instructions): By identifying ainway epithelial regional stem and progenitor cells and elucidating molecular mechanisms regulating their proliferation and differentiation, the studies address multiple outstanding questions central to lung repair and regeneration. The group brings unique skills and resources to the Consortium that will accelerate discovery of new therapies for lung diseases afflicting millions of people.

根据 NHLBI 的数据，气道疾病是美国人因肺部疾病死亡的主要原因。上皮稳态和修复缺陷是许多肺部疾病病理重塑的基础并导致慢性炎症、纤维化和气道阻塞。这样做的总体理由建议采用新的治疗策略来预防或逆转气道病理并改造肺部通过更深入地了解多能干细胞组织将得到极大增强内源性人类区域上皮干细胞，它们如何自我更新，产生定向祖细胞并分化以产生功能性极化上皮。该团队结合了细胞和发育生物学、干细胞生物学和人肺病理学，并利用青蛙、小鼠和三个高度相关的目标的人体模型。目标 1 建立在全面的下一代基础上人支气管 mRNA 和 microRNA (miR) 动态变化的测序数据库上皮细胞在体外进行分化。它检验了特定 MLR 调节的假设粘膜纤毛生成和修复过程中体内祖细胞增殖和细胞命运决定上皮。目标 2 基于对小鼠的研究，描述了大和小上皮祖细胞的特征总是。它将用于细胞分离的新型细胞分选策略与 3D 培养和移植相结合技术来表征人们知之甚少但至关重要的人类小安威祖细胞。下一代 RNA 测序将用于生成 mRNA 的综合数据库这些细胞中的 miR。目标 3 基于显示粒状头样转录动态调节的研究体内气道损伤模型中的因素，并试图了解它们在整合和协调方面的作用修复和再生过程中上皮极性和屏障功能。除了带来独特的检测方法外，向联盟提供模型系统、技术和资源，拟议的实验将提供有关肺干细胞和祖细胞的新数据将有助于指导治疗策略以减轻或预防病变并增强肺部修复、再生和重建。相关性（参见说明）：通过鉴定上皮区域干细胞和祖细胞并阐明分子机制调节它们的增殖和分化，这些研究解决了多个悬而未决的核心问题促进肺部修复和再生。该集团为联盟带来了独特的技能和资源，这将加速发现治疗数百万人肺部疾病的新疗法。