Substrate stiffness regulates alveolar epithelial cell behavior

基质硬度调节肺泡上皮细胞行为

• 批准号: 7777884
• 负责人: GR Scott Budinger
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777884
• 关键词: Acute; Acute Lung Injury; Adenoviruses; Adhesions; Adult Respiratory Distress Syndrome; Alveolar; Animal Model; Animals; Basal lamina; Behavior; Biological Assay; Bleomycin; Cell Differentiation process; Cell Surface Receptors; Cell physiology; Cessation of life; Collagen; Connective Tissue; Data; Deposition; Development; Disease; Disease Progression; Dystroglycan; Environment; Epithelial; Epithelial Cells; Exhibits; Extracellular Matrix; Fibrosis; Future; Growth Factor; Hamman-Rich syndrome; In Situ; In Vitro; Knock-out; Knockout Mice; Laminin; Lung; Lung diseases; Mediating; Mesenchymal; Mortality Determinants; Mus; Myofibroblast; Outcome; Patients; Phenotype; Proteins; Publishing; Pulmonary Fibrosis; Resolution; Respiratory physiology; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Testing; Tissues; alveolar epithelium; base; cell behavior; cell motility; cell type; in vivo; injured; insight; lung injury; migration; mouse model; novel; plectin; public health relevance; receptor; repaired

DESCRIPTION (provided by applicant): In patients with acute lung injury (ALI) or the adult respiratory distress syndrome (ARDS), disordered repair of the injured alveolar epithelium can result in lung fibrosis. Fibrosis is associated with aberrant accumulation of a collagen-rich extracellular matrix in the lung parenchyma that results in tissue stiffness and a progressive decline in lung function. We will test the hypothesis that the tissue in fibrosis induces alveolar epithelial cells (AEC) to deposit matrix enriched in the (3 laminin subunit which functions, via the cell surface receptor dystroglycan and the signaling scaffold protein plectin, to protect AEC from the harmful impact of the fibrotic milieu. To test this hypothesis, in Aim 1, we will assay (3 laminin matrix deposition in situ in normal and fibrotic lungs and in AEC maintained in vitro on substrates of varying stiffness. In Aim 2, we will evaluate the role of ?3 laminin, dystroglycan and plectin in mediating the survival, adhesion, migration, proliferation and differentiation of AEC maintained on substrate of varying stiffness. In Aim 3, we will assess whether the absence of the (3 laminin enhances fibrosis and inhibits disease resolution in two different mouse models of lung disease. In this aim, we propose to use an inducible lung specific (3 laminin subunit knockout mouse line. Lung fibrosis in our knockout and control mice will be initiated by treatment of animals with bleomycin or by the intratracheal instillation of an adenovirus encoding active TGF-(1. Our aims will provide new insights into the mechanisms that underlie the variable development of fibrosis after acute lung injury, a major determinant of outcome in patients with ALI/ARDS. PUBLIC HEALTH RELEVANCE: In certain pulmonary diseases, lung tissue becomes fibrotic and stiffens. We propose to assay how the stiffness of the lung regulates the function of its cellular components. Our results will provide novel insight into the mechanisms of disease progression and has implications for future therapies.

描述（由申请人提供）：在急性肺损伤（ALI）或成人呼吸窘迫综合征（ARDS）患者中，受损肺泡上皮的修复障碍可导致肺纤维化。纤维化与富含胶原的细胞外基质在肺实质中的异常积累相关，其导致组织僵硬和肺功能的进行性下降。我们将检验纤维化组织诱导肺泡上皮细胞（AEC）存款富含β层粘连蛋白亚基的基质的假设，所述β层粘连蛋白亚基通过细胞表面受体肌营养不良蛋白聚糖和信号传导支架蛋白质网蛋白发挥功能，以保护AEC免受纤维化环境的有害影响。为了验证这一假设，在目标1中，我们将在正常和纤维化肺中以及在不同硬度的基质上体外维持的AEC中原位测定β层粘连蛋白基质沉积。在目标2中，我们将评估的作用？3层粘连蛋白、肌营养不良蛋白聚糖和类凝集素介导AEC在不同硬度基质上的存活、粘附、迁移、增殖和分化。在目标3中，我们将评估β层粘连蛋白的缺乏是否在两种不同的肺部疾病小鼠模型中增强纤维化并抑制疾病消退。在这个目标中，我们建议使用诱导型肺特异性β层粘连蛋白亚基敲除小鼠系。在我们的基因敲除小鼠和对照小鼠中，肺纤维化将通过用博来霉素治疗动物或通过肺内滴注编码活性TGF-β 1的腺病毒来启动。我们的目的是提供新的见解，在急性肺损伤后纤维化的变化发展的基础上的机制，在ALI/ARDS患者的结果的主要决定因素。公共卫生相关性：在某些肺部疾病中，肺组织变得纤维化和僵硬。我们建议分析肺的硬度如何调节其细胞成分的功能。我们的研究结果将为疾病进展的机制提供新的见解，并对未来的治疗方法产生影响。