REGULATION OF ALVEOLAR EPITHELIAL CELL PHENOTYPE

肺泡上皮由两种形态不同的分化上皮细胞组成，I型（TI）和II型（TII）细胞，这两种细胞都被认为对正常的肺功能至关重要。尽管正常肺泡上皮的建立和维持对哺乳动物的生命至关重要，但我们对调节这些事件的重要过程的了解有限。该研究的主要目的是了解肺泡上皮细胞的发育和维持是如何受到调控的。在此背景下，该项目的总体目标是阐明TI和TII细胞的细胞系，以及在发育后期负责两种细胞类型分化的细胞机制。大多数关于肺发育的研究都集中在早期发育阶段，特别是分支形态发生的过程。人们对成熟TI和TII细胞的细胞祖细胞知之甚少，也不清楚每种细胞类型的分化是如何发生的。在成人肺中，TII细胞具有修复受损肺泡的能力，获得了TI细胞表型的形态学特征。从30年前进行的实验中使用放射自显影技术和

The alveolar epithelium is comprised of two morphologically distinct differentiated epithelial cells, type I (TI) and type II (TII) cells, both of which are thought to be critical for normal lung function. Although the establishment and maintenance of a normal alveolar epithelium is essential for mammalian life, we have a limited understanding of the important processes that regulate these events. The broad objectives of the research are to understand how alveolar epithelial development and maintenance are regulated. Within this context, the overall goal of this project are to elucidate the cell lineages of TI and TII cells and the cellular mechanisms responsible for the differentiation of both cell types during late development. Most studies of lung development have focused on early developmental stages, in particular the process of branching morphogenesis. Little is understood about the cellular progenitors of mature TI and TII cells or about how differentiation of each of these cell types occurs. In the adult lung, TII cells have the capacity to repair injured alveoli, acquiring morphologic characteristics of the TI cell phenotype. From experiments performed almost 30 years ago using techniques of autoradiography and electron microscopy, it was concluded that a similar process occurred in the developing lung, that TI cells were derived from TII cells. Based on more recent published data and new data presented in the Progress Report and Preliminary Data section, it appears that this pathway may not be the sole or even major mechanism by which TI cells are formed. On the basis of these recent data, we have generated two working hypotheses: 1) during late fetal development, progenitor cells of the alveolar epithelium co-express markers of differentiated TI and TII cells and progressively restrict expression of these markers during differentiation; and 2) type I cells can arise from cells other than or in addition to mature TII cells.