Mechanisms of adult lung alveologenesis

 描述(由申请人提供)：肺功能下降是由于肺泡逐渐丧失而导致的衰老的结果。这种衰弱的过程在肺部疾病的情况下加剧，这些疾病往往是进行性的和致命的。最近的数据表明，成年人类能够产生新的肺组织，以应对外科手术减少的肺体积。这提出了一种令人兴奋的可能性，即在正确的提示下，内源性祖细胞能够恢复患病肺的正常肺泡结构和功能。该项目的目标是确定成人肺中具有产生新肺泡组织能力的上皮干细胞，以及触发这种反应的微环境线索。几个障碍阻碍了之前鉴定人类肺泡干细胞的努力。这些问题包括无法在人类身上进行介入性的纵向损伤/修复研究，人类的肺部与大多数模式生物之间的显著差异，以及缺乏推测的祖细胞群体的区分标记。在这里，将利用两个模型系统的优势来解决这些问题。在特定的目标1中，遗传易驯化的小鼠将被用来在单细胞水平上识别 有能力产生新的肺泡上皮的细胞。由于猕猴的肺在细胞水平上与人类的肺在细胞水平上比大多数模式生物更相似，因此通过对小鼠的功能研究确定的机制将用肺切除猕猴的数据进行验证。在特定的目标2中，将使用遗传功能丧失实验来检验Notch的假设，即Notch由再生生态位的局部成纤维细胞成分提供，对成人新的肺泡上皮的生成至关重要。在具体目标3中，将利用小鼠的遗传功能丧失和骨髓移植来验证AEC2通过分泌CCL2将单核细胞招募到PNX后肺内的假设。在肺中，IL13将这些细胞极化为伤口愈合的“M2”表型，以促进成人肺泡生成。总而言之，这种全面的、多组织的方法将解决围绕成人肺再生机制的知识空白。这些数据将提供新的细胞和分子靶点，可用于预防或逆转与肺泡破坏相关的肺功能下降。

 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.