Mechanisms of adult lung alveologenesis

成人肺泡发生的机制

• 批准号: 9058135
• 负责人: Jason Randall Rock
• 金额: $ 55.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058135
• 关键词: Address; Adult; Aging; Alveolar; Alveolus; Animal Model; Architecture; Biological Assay; Biological Models; Bone Marrow Transplantation; CCL2 gene; Cells; Cues; Data; Development; Embryo; Employee Strikes; Epithelial; Epithelial Cells; Event; Fibroblasts; Future; Generations; Genetic; Goals; Health; Human; Immune; Individual; Injury; Interleukin-13; Knock-out; Knowledge; Label; Lung; Lung diseases; Macaca; Macaca mulatta; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Natural regeneration; Notch Signaling Pathway; Operative Surgical Procedures; Organism; Pathway interactions; Phenotype; Pneumonectomy; Population; Primates; Process; Property; Recruitment Activity; Regenerative response; Respiratory physiology; Rodent; Signal Pathway; Staging; Stem cells; Structure of parenchyma of lung; Surface Antigens; Testing; Tissues; Translating; Wound Healing; alveolar destruction; alveolar epithelium; cell type; cellular targeting; effective therapy; improved; in vivo; loss of function; lung regeneration; lung volume; macrophage; monocyte; mortality; notch protein; novel; polarized cell; prevent; regenerative; research study; response; transcription factor

 DESCRIPTION (provided by applicant): Declining lung function is a consequence of aging that results from the gradual loss of alveoli. This debilitating process is exacerbated in the context of lung diseases that are oftentimes progressive and fatal. Recent data suggest that adult humans are capable of generating new lung tissue in response to a surgical reduction in lung volume. This raises the exciting possibility that, given the right cues, endogenous progenitor cells could be capable of restoring normal alveolar architecture and function in diseased lungs. The objective of this project is to identify epithelial stem cells in the adult lun that have the capacity to generate new alveolar tissue and the microenvironmental cues that trigger this response. Several obstacles have impeded previous efforts to identify human alveolar stem cells. These include the inability to perform interventional, longitudinal injury/repir studies in humans, striking dissimilarities between the lungs of humans and most model organisms, and a paucity of discriminating markers for putative progenitor cell populations. Here, the advantages of two model systems will be exploited to address these issues. In Specific Aim 1, the genetically tractable mouse will be used to identify, at the single cell level, cells with the ability to generate new alveolar epithelium. Because the lungs of rhesus macaques are more similar at the cellular level to those of humans than most model organisms, the mechanisms identified through functional studies in mice will be validated with data from pneumonectomized macaques. In Specific Aim 2, genetic loss of function experiments will be used to test the hypothesis that Notch, provided by the local fibroblast component of the regenerative niche, is critical for the generation of new alveolar epithelium in adults. In Specifi Aim 3, genetic loss of function and bone marrow transplants in mice will be used to test the hypothesis that AEC2 recruit monocytes to the lung post-PNX through the secretion of Ccl2. In the lung, IL13 polarizes these cells toward a wound healing "M2" phenotype to promote adult alveologenesis. Together, this comprehensive, multi-organismal approach will address knowledge gaps surrounding the mechanisms of lung regeneration in adults. These data will provide novel cellular and molecular targets that can be leveraged to prevent or reverse the decline in lung function associated with the destruction of alveoli.

 描述（由适用提供）：肺功能下降是由于肺泡的年级损失而导致的衰老的结果。在肺部疾病的背景下，这种衰弱的过程加剧了，这些肺部疾病通常是进步和致命的。最近的数据表明，成年人能够响应肺部手术减少而产生新的肺组织。这增加了令人兴奋的可能性，鉴于正确的提示，内源性祖细胞可能能够恢复肺部肺部正常的肺泡结构和功能。该项目的目的是鉴定成年LUN中的上皮干细胞，这些干细胞具有产生新的肺泡组织和触发这种反应的微环境提示。几个障碍阻碍了以前识别人肺泡干细胞的努力。这些包括无法对人类进行介入，纵向损伤/回应研究，在人类和大多数模型组织之间的差异以及对推定祖细胞群体的区分标记的差异。在这里，将探索两个模型系统的优势来解决这些问题。在特定的目标1中，一般可牵引的鼠标将用于在单个单元格级别识别 具有产生新的肺泡上皮的能力的细胞。由于恒河猕猴在细胞水平上的肺部与人类的肺部比大多数模型生物更相似，因此通过在小鼠的功能研究中鉴定的机制将通过肺切除猕猴的数据验证。在特定的目标2中，将使用功能实验的遗传丧失来检验以下假设：再生生物的局部成纤维细胞成分提供的Notch对于成人新的肺泡上皮的产生至关重要。在特定目标3中，小鼠功能的遗传丧失和骨髓移植将用于检验以下假设：AEC2通过CCL2的分泌将单核细胞募集到肺后-PNX。在肺中，IL13将这些细胞偏向伤口愈合的“ M2”表型，以促进成人肺泡术。总之，这种全面的多生物方法将解决围绕成人肺部再生机制的知识差距。这些数据将提供可利用的新细胞和分子靶标，以防止或扭转与肺泡破坏相关的肺功能下降。