An Integrated Approach to Airway Epithelial Repair and Regeneration

气道上皮修复和再生的综合方法

• 批准号: 8223930
• 负责人: BRIGID L.M. HOGAN
• 金额: $ 70.77万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/8223930
• 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; 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

DESCRIPTION (provided by applicant): 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 miRs 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 airways. It combines novel cell sorting strategies for cell isolation with 3D culture and transplantation techniques to characteriz poorly understood, but critically important, human small airway 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 airway pathology and to enhance lung repair, regeneration and reconstruction. RELEVANCE (See instructions): By identifying airway 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.

描述（由申请人提供）：根据 NHLBI，气道疾病是美国肺病死亡的主要原因。 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。该提案的总体基本原理是，通过更深入地了解内源性人类区域上皮干细胞，以及它们如何自我更新、产生定型的细胞因子，预防或逆转气道病理学以及利用多能干细胞改造肺组织的新治疗策略将得到极大增强。祖细胞并分化形成功能性极化上皮。该团队结合了细胞和发育生物学、干细胞生物学和人类肺部病理学方面的专业知识，并在三个高度相关的目标中利用青蛙、小鼠和人类模型。 Aim 1 建立在一个全面的下一代测序数据库的基础上，该数据库记录了体外分化的人支气管上皮细胞中 mRNA 和 microRNA (miR) 的动态变化。它检验了特定 miR 调节祖细胞增殖和细胞命运决定的假设。 体内粘液纤毛上皮的生成和修复过程中。目标 2 基于对小鼠大气道和小气道上皮祖细胞特征的研究。它将用于细胞分离的新颖细胞分选策略与 3D 培养和移植技术相结合，以表征人们知之甚少但至关重要的人类小气道祖细胞。 然后，下一代 RNA 测序将用于生成这些细胞中 mRNA 和 miR 的综合数据库。目标 3 基于体内气道损伤模型中粒状头样转录因子动态调节的研究，旨在了解它们在修复和再生过程中整合和协调上皮极性和屏障功能的作用。除了为联盟带来独特的测定、模型系统、技术和资源外，拟议的实验还将提供有关肺干细胞和祖细胞的新数据，这将有助于指导减轻或预防气道病理并增强肺修复、再生和治疗的治疗策略。重建。相关性（参见说明）：通过鉴定气道上皮区域干细胞和祖细胞并阐明调节其增殖和分化的分子机制，这些研究解决了肺修复和再生的多个重要问题。该小组为联盟带来了独特的技能和资源，将加速发现治疗数百万人肺部疾病的新疗法。