Cellular and molecular mediators of alveolar septum formation and regeneration

对气体交换区造成不可逆转破坏的肺部疾病是一种重大且日益加重的疾病负担。为了开发新的再生治疗破坏性肺部疾病，需要破译肺生长和再生的基本机制。本项目的目的是研究我们之前发现的肺泡化候选基因的作用及其对肺泡间充质细胞分化和功能的影响，以深入了解控制出生后肺生长、结构维持和再生的机制。肺泡成纤维细胞是分离过程所必需的，阻止肺泡成纤维细胞分化完全阻断了肺泡形成。假设表达PDGFR-α的成纤维细胞前体随后衍生出含脂成纤维细胞（脂肪成纤维细胞）以及肺泡间隔的肌成纤维细胞。我们的目标是剖析肺泡成纤维细胞在出生后和再生肺生长中的作用，通过miRNA和蛋白质组分析跟踪脂质和肌成纤维细胞从PDGFRa阳性前体的分化过程，通过细胞类型特异性启动子驱动基因表达特异性靶向每种成纤维细胞亚型，包括祖细胞。并进行体内细胞命运追踪研究，以解决生理或病理条件下从一种成纤维细胞类型向另一种成纤维细胞类型的转变。为此，采用肺切除术后和热量限制/再喂养肺泡隔再生模型。体内功能丧失研究将解决已确定的靶基因在出生后和成人再生肺泡形成中的作用。

Lung diseases that cause irreversible destruction of gas exchange regions represent a significant and increasing disease burden. In order to develop new regenerative therapies for destructive lung diseases the basic mechanisms of lung growth and regeneration need to be deciphered. The objective of this project is to investigate the role of candidate genes of alveolarization which were previously identified by us and their impact on alveolar mesenchymal cell differentiation and function in order to gain insight into the mechanisms that control postnatal lung growth, structural maintenance and regeneration. Alveolar fibroblasts are necessary for the process of septation as prevention of alveolar fibroblast differentiation completely blocked alveolarization. It is assumed that PDGFR-α expressing fibroblast precursors subsequently derive lipid containing fibroblasts (lipofibroblasts) as well as myofibroblasts of the alveolar septum. We aim to dissect the role of alveolar fibroblasts in postnatal and regenerative lung growth, to follow the differentiation process of lipo- and myofibroblasts from their PDGFRa positive precursors by miRNA and proteome analysis, to specifically target each fibroblast subtype including the progenitor cells by cell type specific promoter driven gene expression, and to perform in vivo cell fate tracing studies to address transitions from one fibroblast cell type to another under physiological or pathological conditions. To this end, post-pneumectomy and caloric restriction/refeeding models of alveolar septum regeneration are employed. In vivo loss of function studies will address the role of identified target genes in postnatal and adult regenerative alveolarization.