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，气道疾病是由于肺部疾病而导致美国死亡的主要原因。 上皮稳态的缺陷和修复基础的病理学重塑基础，在许多肺部疾病中发现，并导致慢性炎症，纤维化和气道阻塞。该提案的总体理由是，通过对内源性人类区域上皮干细胞的更透彻的了解，它们如何自我更新，产生忠实的祖细胞并脱离功能上的极性上皮，可以极大地增强，以预防或逆转多元干细胞的新型治疗策略以及从多能干细胞中锻炼肺组织的新型治疗策略。该小组将细胞和发育生物学，干细胞生物学和人类肺病理生物学方面的专业知识结合在一起，并以三个高度相互关联的目的利用青蛙，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基于人支气管上皮细胞中MRNA和microRNA（miRS）的动态变化的数据库，并在体外分化。它检验了以下假设：特定miR调节祖细胞增殖和细胞命运决策 在粘膜上皮的生成和修复过程中的体内。 AIM 2基于对大小气道中上皮祖细胞的小鼠的研究。它结合了新颖的细胞分选策略，将细胞分离与3D培养物和移植技术与特征差的理解较低，但至关重要的人类小型气道祖细胞。 然后，下一代RNA测序将用于在这些细胞中生成mRNA和miR的全面数据库。 AIM 3是基于显示体内气道损伤模型中粒状头部（例如转录因子）的动态调节的研究，并试图了解其在修复和再生过程中整合和坐标上皮的极性和屏障功能的作用。除了将独特的测定，模型系统，技术和资源带到财团外，拟议的实验还将提供有关肺部干和祖细胞细胞的新颖数据，这些数据将有助于指导治疗策略，以减轻或防止气道病理，并增强肺修复，再生，再生和重建。相关性（请参阅说明）：通过识别气道上皮区域茎和祖细胞以及阐明调节其增殖和分化的分子机制，这些研究解决了对肺修复和再生的核心核心问题。该小组将独特的技能和资源带给财团，这将加速发现灾害数百万人的肺部疾病的新疗法。