Epithelial Mesenchymal Transition in Pulmonary Fibrosis

肺纤维化中的上皮间质转化

• 批准号: 8605207
• 负责人: Harold A Chapman
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605207
• 关键词: Address; Alveolar; Automobile Driving; Basement membrane; Binding; Biological Assay; Biological Markers; Biopsy; Bleomycin; Cells; Complex; DNA; DNA Binding; Deposition; Epithelial; Epithelial Cells; Event; Exercise; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Gene Targeting; Generations; Goals; Growth Factor; Hamman-Rich syndrome; Human; Inflammation; Injury; Integrins; Laminin; Laminin Receptor; Lasers; Lead; Link; Lung; Maps; Mediator of activation protein; Mesenchymal; Modeling; Mus; Myofibroblast; Nuclear; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phosphorylation; Phosphotransferases; Process; Production; Progress Reports; Proliferating; Protein Tyrosine Kinase; Pulmonary Fibrosis; Regulation; Role; Series; Signal Pathway; Signal Transduction; Site; Source; System; Testing; Tissues; Toxic effect; Tyrosine; Uncertainty; Wound Healing; base; cell growth; chromatin immunoprecipitation; cytokine; defined contribution; design; effective therapy; epithelial to mesenchymal transition; fibrogenesis; in vivo; indium-bleomycin; injured; lung repair; mutant; promoter; public health relevance; research study; response; response to injury; therapeutic target; Address; Alveolar; Automobile Driving; Basement membrane; Binding; Biological Assay; Biological Markers; Biopsy; Bleomycin; Cells; Complex; DNA; DNA Binding; Deposition; Epithelial; Epithelial Cells; Event; Exercise; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Gene Targeting; Generations; Goals; Growth Factor; Hamman-Rich syndrome; Human; Inflammation; Injury; Integrins; Laminin; Laminin Receptor; Lasers; Lead; Link; Lung; Maps; Mediator of activation protein; Mesenchymal; Modeling; Mus; Myofibroblast; Nuclear; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phosphorylation; Phosphotransferases; Process; Production; Progress Reports; Proliferating; Protein Tyrosine Kinase; Pulmonary Fibrosis; Regulation; Role; Series; Signal Pathway; Signal Transduction; Site; Source; System; Testing; Tissues; Toxic effect; Tyrosine; Uncertainty; Wound Healing; base; cell growth; chromatin immunoprecipitation; cytokine; defined contribution; design; effective therapy; epithelial to mesenchymal transition; fibrogenesis; in vivo; indium-bleomycin; injured; lung repair; mutant; promoter; public health relevance; research study; response; response to injury; therapeutic target

DESCRIPTION (provided by applicant): Alveolar epithelial cells (AEC) contribute to lung repair responses by proliferating, regulating matrix resorption, and presenting active TGF(1 to fibroblasts, promoting their conversion to myofibroblasts. AECs may also exercise their own plasticity to become fibroblast-like in their invasiveness and matrix production a process termed epithelial to mesenchymal-like transitions (EMT). While many lines of evidence link persistent active TGF(1 to the pathobiology of lung fibrosis, prolonged global inhibition of TGF(1 signaling is likely to have unacceptable toxicities. A more targeted therapeutic approach to blockade of TGF(1 signaling is needed. Recent findings identify a (1 integrin-dependent specific signaling pathway involving crosstalk between a tyrosine phosphorylated (-catenin (pY654) and Smad signaling that drives, and is required for, AEC EMT ex vivo and in vivo during fibrogenesis in mice. These observations lead to the hypothesis that dysregulated accumulation of nuclear pY654-(-catenin/pSmad2 complexes in AECs drives EMT, expands myofibroblasts, and results in progressive pulmonary fibrosis. This hypothesis is addressed in the application by a series of experiments designed to dissect and elucidate the key signaling events of EMT and myofibroblast expansion downstream of formation of (-catenin/pSmad2 complexes. It is postulated that pSmad2 functions as a key switch to either suppress EMT and fibrosis or, when complexed with pY654-(-catenin, switch on reprogramming leading to EMT. To test this hypothesis, mice with conditional deletion in vivo of the key components of the proposed signaling pathway will be used, along with a fate-mapping system to quantify EMT in vivo. Important gene targets of (-catenin/pSmad2 complexes in AECs and myofibroblasts will be defined through promoter analyses and direct DNA binding assays (chromatin immunoprecipitation). Biomarkers of the pathway driving EMT defined in mice will then be used to assess the activity of the (-catenin/pSmad2 pathway in human lungs. Collectively, these experiments should clarify important uncertainties regarding the role of EMT in pulmonary fibrosis, including Idiopathic Pulmonary Fibrosis (IPF). If the hypotheses prove largely correct, the studies should define a specific TGF(1-driven signaling pathway that could be quantified in IPF patients and serve as a basis for targeted therapy, avoiding the toxicities of prolonged global inhibition of TGF(1 signaling.

描述（由申请人提供）：肺泡上皮细胞（AEC）通过增殖，调节基质吸收和呈现主动TGF来促进肺修复反应（1至成纤维细胞，促进其转化为肌纤维细胞。间充质样过渡（EMT），而许多证据链接持续的主动TGF（与肺纤维化的病理生物学1，全球抑制TGF的延长（1信号传导可能具有不可接受的毒性。酪氨酸磷酸化（-Catenin（Py654）和Smad信号传导，在小鼠纤维化期间驱动和必需的AEC EEC EMT和体内所必需。这些观察结果导致核PY654-（-Catenin/Psmad2 Complecters in aeecs in a aeecs and a e emef sefime y em em imef ysef seflive remt sefime imef ysef ysef ysef sefime y ybl y ybbl osef ysef seflive ysef sefime y rem try的假说肺纤维化。该假设在应用中通过一系列旨在解剖和阐明EMT和肌纤维细胞扩展的关键信号事件的一系列实验来解决。该假设将使用所提出的信号通路的关键组成部分的有条件缺失的小鼠，以及量化EMT在体内的命运映射系统（-catenin/psmad2 complection）在AEC中的重要基因靶标。然后，将使用小鼠定义的驱动EMT驱动EMT来评估人类肺中的（ - 帕宁蛋白/PSMAD2途径的活性。总的来说，这些实验应阐明有关EMT在肺纤维化中的作用的重要不确定性，包括特发性肺纤维化（IPF）。如果假设在很大程度上是正确的，则研究应定义特定的TGF（1个驱动的信号通路，可以在IPF患者中进行量化，并作为靶向治疗的基础，避免了延长全球TGF的毒性（1个信号传导。