Differentiation of Alveolar Epithelium in Pulmonary Fibrosis

肺纤维化中肺泡上皮的分化

• 批准号: 7708480
• 负责人: Philip L. Sannes
• 金额: $ 7.45万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-11 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708480
• 关键词: AGTR2 gene; Address; Affect; Alveolar; Alveolar Cell; Alveolus; Anabolism; Basement membrane; Cell Differentiation process; Cells; Data; Development; Disease; Effectiveness; Environment; Epithelial; Epithelial Cells; Event; Exhibits; Extracellular Matrix; Family; Fibroblast Growth Factor; Fibroblasts; Fibrosis; Gene Expression Regulation; Generations; Glycoproteins; Grant; Growth Factor; Hamman-Rich syndrome; Histocytochemistry; Human; Hyperplasia; Injury; Inorganic Sulfates; Lesion; Link; Lung; Lung diseases; Mesenchymal; Mucous body substance; Nuclear; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Prevention; Process; Proliferating; Pulmonary Fibrosis; Rattus; Reaction; Regulatory Pathway; Relative (related person); Respiratory physiology; Signal Pathway; Signal Transduction; Staging; Stimulus; Surface; Tissues; Transcription Factor 3; Undifferentiated; Unspecified or Sulfate Ion Sulfates; Work; Wound Healing; abstracting; alveolar epithelium; alveolar type II cell; base; cell type; daughter cell; in vitro Model; in vivo Model; injured; interstitial; loss of function; novel; prevent; public health relevance; repaired; response; sulfation; sulfotransferase; transcription factor

DESCRIPTION (provided by applicant): Early events in the pathogenesis of interstitial pulmonary fibrosis (IPF) have been linked to faulty repair of injured alveolar epithelium where proliferating alveolar type II (AT2) cells do not effectively differentiate into type I (AT1) cells. This leads to irreversible damage, fibrosis, and loss of function. The mechanisms that normally control the process of differentiation of AT2 cells into AT1s are poorly understood, so regulatory molecules or pathways that are affected by these pathogenic events have not been elucidated. In this proposal, we will apply new concepts developed from recent in vitro modeling of normal human alveolar epithelial cell differentiation and in vivo modeling of pulmonary fibrosis is rats to study novel, interactive signaling pathways and nuclear factors that we predict are incorrectly regulated in fibrotic lung diseases, such as idiopathic pulmonary fibrosis. Our data indicates that excessive increases in sulfated extracellular matrix (ECM) as seen in pulmonary fibrosis, alters the effectiveness of key factors in the differentiation process, FoxA1 and Wnt7A, and stimulates a shift to regulatory factors which favor proliferation even in a high sulfated ECM environment. We will show that FoxA2, known to compensate for ineffective FoxA1 in development, is favored under these conditions and upregulates Wnt7B, which promotes proliferation over differentiation. Instead of stabilization of proliferation and phenotype, alveolar epithelial cells continue to attempt to achieve differentiation by producing more TGF2, which not only sustains the problem but promotes EMT and more fibrosis. The SPECIFIC HYPOTHESIS to be addressed is: The excessively high level of sulfated ECMs in interstitial pulmonary fibrosis favors sustained expression of FoxA2 and promotes TGF? signaling in alveolar epithelium, which together increase Wnt7B expression and signaling resulting in sustained proliferation, stalled differentiation, and prevention of the generation of fully mature AT1 cells. To address this hypothesis, we will examine the levels of expression of each of these and related molecules by histochemistry in patients with mild or severe stages of IPF. Results of these studies are expected to support the fundamental hypothesis that fixed whole and shed fragments of pericellular sulfated components of extracellular matrices alter the microenvironment of alveolar epithelial cells - which constitutes a critical determinant of how these cells interact, their proliferative potential, and differentiated fate by influencing defined responses to WNT and TGF2 signaling and specific gene regulation. They will provide essential information needed to better understand basic cell-cell and cell-ECM relationships in pulmonary fibrosis and the mechanisms that steer its pathogenesis. PUBLIC HEALTH RELEVANCE: Pulmonary fibrosis is a disease of unknown origin which causes stiffening of internal surfaces of the lung, which significantly reduces lung function. A potentially significant contributing factor to the development of fibrotic lung disease may the impaired ability of cells which line internal surfaces of the lung to renew themselves by dividing and differentiating. This grant will define specific changes in the expression of modulatory influences which prevent cells from effectively differentiating and promote tissue scaring. (End of Abstract)

描述（由申请人提供）： 间质性肺纤维化（IPF）发病机制中的早期事件与受损肺泡上皮的错误修复有关，其中增殖的肺泡II型（AT 2）细胞不能有效分化为I型（AT 1）细胞。这会导致不可逆的损伤、纤维化和功能丧失。通常控制AT 2细胞分化为AT 1的过程的机制知之甚少，因此受这些致病事件影响的调节分子或途径尚未阐明。在这项提案中，我们将应用新的概念，从最近在体外建模的正常人肺泡上皮细胞分化和在体内建模的肺纤维化是大鼠研究新的，相互作用的信号通路和核因子，我们预测是不正确的调节纤维化肺疾病，如特发性肺纤维化。我们的数据表明，如在肺纤维化中所见，硫酸化细胞外基质（ECM）的过度增加改变了分化过程中关键因子FoxA 1和Wnt 7A的有效性，并刺激向调节因子的转变，即使在高硫酸化ECM环境中也有利于增殖。我们将证明，FoxA 2，已知补偿无效的FoxA 1在发展中，是有利的，在这些条件下，上调Wnt 7 B，促进增殖分化。肺泡上皮细胞继续试图通过产生更多的TGF 2来实现分化，而不是稳定增殖和表型，这不仅维持了问题，而且促进了EMT和更多的纤维化。要解决的具体假设是：肺间质纤维化中硫酸化ECM水平过高有利于FoxA 2的持续表达，并促进TGF？在肺泡上皮细胞中的Wnt 7 B表达和信号传导，其一起增加Wnt 7 B表达和信号传导，导致持续增殖、停滞分化和阻止完全成熟的AT 1细胞的产生。为了解决这一假设，我们将通过组织化学检查轻度或重度IPF患者中这些分子和相关分子的表达水平。这些研究的结果预计将支持的基本假设，即固定的整体和脱落片段的细胞外基质的细胞周围硫酸化成分改变肺泡上皮细胞的微环境-这构成了一个关键的决定因素，这些细胞如何相互作用，其增殖潜力，并通过影响定义的响应WNT和TGF 2信号和特定的基因调控分化的命运。它们将提供更好地理解肺纤维化中基本细胞-细胞和细胞-ECM关系以及引导其发病机制所需的基本信息。 公共卫生关系：肺纤维化是一种原因不明的疾病，其导致肺内表面硬化，从而显著降低肺功能。纤维化肺疾病发展的一个潜在的重要因素可能是排列在肺内表面的细胞通过分裂和分化自我更新的能力受损。这项资助将定义调节影响表达的具体变化，这些影响阻止细胞有效分化并促进组织瘢痕形成。 (End摘要）