Mechanisms of adult lung alveologenesis

 描述（由申请人提供）：肺功能下降是肺泡逐渐丧失导致的衰老的结果。这种使人衰弱的过程在肺部疾病的情况下加剧，这些疾病通常是渐进的和致命的。最近的数据表明，成年人能够产生新的肺组织，以响应肺体积的手术减少。这提出了一个令人兴奋的可能性，即如果给予正确的提示，内源性祖细胞可能能够恢复病变肺中正常的肺泡结构和功能。本项目的目的是鉴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。一些障碍阻碍了以前的努力，以确定人类肺泡干细胞。这些问题包括无法在人体中进行干预性纵向损伤/排斥研究，人类和大多数模式生物的肺之间存在显著差异，以及缺乏用于推定祖细胞群体的鉴别标记。在这里，两个模型系统的优势将被利用来解决这些问题。在具体目标1中，遗传学上易处理的小鼠将用于在单细胞水平上鉴定， 具有生成新肺泡上皮细胞能力的细胞。由于恒河猴的肺在细胞水平上比大多数模式生物更类似于人类的肺，因此通过小鼠功能研究确定的机制将用来自肺切除猕猴的数据进行验证。在特定目标2中，将使用遗传功能丧失实验来检验以下假设：由再生小生境的局部成纤维细胞组分提供的Notch对于成人中新肺泡上皮的生成至关重要。在具体目标3中，将使用小鼠中的遗传功能丧失和骨髓移植来检验AEC 2通过分泌Ccl 2将单核细胞募集到PNX后的肺中的假设。在肺中，IL 13使这些细胞朝向伤口愈合“M2”表型极化以促进成人肺泡形成。总之，这种全面的多生物体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.