Cellular and molecular mediators of alveolar septum formation and regeneration

点击翻译按钮获取中文摘要

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.