Epithelial Progenitor Cells in Lung Repair and Regeneration

上皮祖细胞在肺修复和再生中的作用

• 批准号: 8598931
• 负责人: PAO-TIEN CHUANG
• 金额: $ 63.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/8598931
• 关键词: Adult; Alveolar; Alveolar Cell; Biological; Biological Assay; Biology; Cells; Cellular biology; Clinical; Distal; Embryo; Epithelial; Epithelial Cells; Flow Cytometry; Genomics; Goals; Human; Image; Instruction; Kidney; Lung; Lung diseases; Maintenance; Modeling; Mus; Neuroendocrine Cell; Organoids; Principal Investigator; Pulmonary Emphysema; Pulmonary Fibrosis; Research Infrastructure; Research Personnel; Source; Stem cells; Structure of parenchyma of lung; Techniques; Technology; Testing; Therapeutic; Time; Translations; Transplantation; adhesion receptor; alveolar epithelium; base; capsule; clinical infrastructure; empowered; human disease; in vivo; innovation; interest; lung development; lung imaging; lung injury; lung regeneration; lung repair; miniaturize; novel; progenitor; programs; reconstitution; repaired; respiratory; tool; vascular bed

The pulmonary bronchiolar and alveolar epithelia are involved prominently in a number of important human diseases associated with loss of alveolar integrity, including emphysema and pulmonary fibrosis. In each of these conditions the capacity to generate new alveolar epithelium, and its associated vascular bed, would be of great potential therapeutic value, but such capacity remains beyond the reach of current technology. This application is predicated on the idea that better understanding of distal ainA/ay and alveolar epithelial cell progenitor biology is a crucial part of any effort to move the field of directed distal lung remodeling or repair toward the clinical arena. Toward that end, this application brings together investigative groups with different expertise but overiapplng interests in epithelial progenitor cell biology to advance the understanding of distal lung development, maintenance, and repair. The major objectives are (1) To define the transcriptional program of heretofore uncharacterized distal airway and alveolar progenitors and test the hypothesis that differential expression of adhesion receptors underiies the capacity of epithelial subtypes to self-organize and promote repair. (2) Define the requirement for neuroendocrine cells (PNECS )and alveolar progenitor cells in maintenance and reconstitution of distal airway and alveolar cells following lung injury. (3) Analyze and further develop a novel, single cell in vivo lung organoid assay in kidney capsules in order to optimize the capacity of adult epithelial progenitor cells to generate functional respiratory units de novo. Important tools and approaches developed to achieve these aims include mice with inducible cre activity knocked into lineage-defining genomic loci, flow cytometry-based techniques to isolate and transcriptionally profile mouse and human embryonic and adult epithelial progenitors, and innovative imaging that allows real time capture of stable images of lung and lung organoids over time. We anticipate that by the completion of these studies we should be able to adapt our in vivo assay toward orthotopic transplantation of cellular units capable of lung development. Overall, these studies should provide crucial conceptual and technological infrastructure for the clinical translation of progenitor cell biology to human lung disease. RELEVANCE (See instructions); This proposal brings together several investigators with overiapplng but distinct expertise in the field of epithelial cell biology with the goal of generating the conceptual biological infrastructure as well as technology for creating distal lung tissue de novo from a source of progenitor cells. The projects should empower translation of new concepts to the treatment of lung diseases.

肺细支气管和肺泡上皮细胞在许多重要的人类疾病中起着显着的作用。 与肺泡完整性丧失相关的疾病，包括肺气肿和肺纤维化。在每个 在这些条件下，产生新肺泡上皮及其相关血管床的能力将是 具有巨大的潜在治疗价值，但这种能力仍然超出了当前技术的能力范围。这 应用的基础是更好地理解远端 ainA/ay 和肺泡上皮细胞 祖生物学是任何推动定向远端肺重塑或修复领域努力的关键部分 走向临床舞台。为此，该应用程序汇集了不同领域的调查小组 对上皮祖细胞生物学的专业知识和过度兴趣，以促进对远端细胞的理解 肺的发育、维护和修复。主要目标是 (1) 定义转录 迄今为止未表征的远端气道和肺泡祖细胞的程序并检验以下假设 粘附受体的差异表达是上皮亚型自组织能力的基础 并促进修复。 (2)明确神经内分泌细胞(PNECS)和肺泡祖细胞的需求 细胞在肺损伤后维持和重建远端气道和肺泡细胞。 (3) 分析 并进一步开发肾胶囊中的新型单细胞体内肺类器官测定，以优化 成体上皮祖细胞从头产生功能性呼吸单位的能力。重要的 为实现这些目标而开发的工具和方法包括将诱导性 Cre 活性敲入的小鼠 谱系定义基因组位点，基于流式细胞术的技术来分离和转录分析小鼠 以及人类胚胎和成人上皮祖细胞，以及允许实时捕获的创新成像 随着时间的推移，肺和肺类器官的稳定图像。我们预计，通过完成这些 研究表明我们应该能够使我们的体内测定适应细胞单元的原位移植 肺部有能力发育。总的来说，这些研究应该提供重要的概念和技术 将祖细胞生物学临床转化为人类肺部疾病的基础设施。 相关性（参见说明）； 该提案汇集了几位在该领域具有广泛但独特专业知识的研究人员 上皮细胞生物学，目标是生成概念性生物基础设施以及 利用祖细胞来源从头创建远端肺组织的技术。项目应 使新概念转化为肺部疾病的治疗。