REGULATION OF ALVEOLAR EPITHELIAL CELL PHENOTYPE

肺泡上皮细胞表型的调节

• 批准号: 6930097
• 负责人: LELAND George DOBBS
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-09 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930097
• 关键词: biological signal transduction; biomarker; cell differentiation; confocal scanning microscopy; developmental genetics; gene expression; genetic markers; genetic regulatory element; genetic transcription; genetically modified animals; laboratory mouse; lung alveolus; lung development; microarray technology; phenotype; respiratory epithelium; tissue /cell culture

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.

肺泡上皮由两种形态上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是正常肺功能的关键。虽然正常肺泡上皮细胞的建立和维持对哺乳动物的生命是必不可少的，但我们对调节这些事件的重要过程的了解有限。这项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调节的。在此背景下，该项目的总体目标是阐明TI和TII细胞的细胞谱系以及在发育后期负责这两种细胞类型分化的细胞机制。肺发育的大多数研究都集中在早期发育阶段，特别是分支形态发生的过程。关于成熟TI和TII细胞的细胞祖细胞或关于这些细胞类型中的每一种的分化如何发生的了解很少。在成人肺中，TII细胞具有修复受损肺泡的能力，获得TI细胞表型的形态学特征。从近30年前使用放射自显影技术进行的实验中， 通过电镜观察，可以得出结论，在发育中的肺中发生了类似的过程，即TI细胞来源于TII细胞。基于最近发表的数据和进展报告和初步数据部分中提供的新数据，似乎该途径可能不是TI细胞形成的唯一甚至主要机制。基于这些最新的数据，我们提出了两个工作假设：1）在胎儿发育后期，肺泡上皮祖细胞共表达分化的TI和TII标记物 I型细胞可以产生于成熟TII细胞之外的细胞或除成熟TII细胞之外的细胞。