Function of epithelial-mesenchymal transition during pulmonary fibrosis

上皮间质转化在肺纤维化过程中的作用

• 批准号: 8821656
• 负责人: KEVIN KEEWOUN KIM
• 金额: $ 38.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821656
• 关键词: Address; Affect; Alveolar; Animal Model; Bleomycin; Bone Marrow; Cell Culture Techniques; Cells; Cessation of life; Chronic Disease; Cicatrix; Clinical; Coculture Techniques; Collagen; Collagen Gene; Collagen Type I; Complication; Consensus; Data; Deposition; Development; Diagnosis; Disease; Embryonic Development; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Extracellular Matrix; Family; Fibrillar Collagen; Fibroblasts; Fibrosis; Goals; Hamman-Rich syndrome; Helix-Turn-Helix Motifs; Human; Injury; Investigation; Lead; Learning; Lung; Measures; Medical; Mesenchymal; Morbidity - disease rate; Mus; Myofibroblast; Pathway interactions; Phenotype; Play; Process; Proteins; Pulmonary Fibrosis; Recovery; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Signaling Molecule; Source; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Work; cell behavior; cell type; design; fibrogenesis; human disease; interstitial; migration; novel; programs; repaired; therapeutic target; transcription factor; tumor progression

DESCRIPTION (provided by applicant): The goal of this application is to define the role of different cell types, particularly lung epithelial cells, in the development pulmonary fibrosis. Progressive fibrosis is a common feature of many chronic diseases leading to significant morbidity and death. Fibrosis can also occur without any known cause in diseases such as Idiopathic Pulmonary Fibrosis (IPF). IPF is a devastating disease that affects greater than 5 million people world-wide. The median survival is 3-5 years from time of diagnosis and current medical therapy is largely ineffective. Despite intense investigation, we still have a poor understanding into the mechanisms that regulate fibrosis and even fundamental questions such as which cells produce the collagen-rich scar remain unanswered. Prior work has focused mainly on the function of fibroblasts. However, a new paradigm is emerging in which the function of epithelial cells plays a critical role in determining the progression of fibrogenesis. This possibility is exciting because the role of epithelial cells is undefined and a clearer understanding of the mechanisms that regulate epithelial cell behavior has the potential of offering new targets for better therapeutic intervention. We have developed several techniques in the last few years to define the function and regulation of lung epithelial cells during fibrogenesis. Using animal models, we and others have found that during fibrogenesis, epithelial cells are capable of transitioning into fibroblast-like cells in a process of epithelial-mesenchyma transition (EMT). During EMT, lung epithelial cells may acquire the ability to produce type I collagen which is the major component of the fibrotic scar. The extent to which lung epithelial cells or any other cell type contributes to the collagen-rich fibrosis remains unknown and we have generated a mouse in which we can delete the type I collagen gene in different cell types. Thus, we will be able to definitively determine which cell type(s) contribute directly to collagen synthesis during fibrogenesis. Lung epithelial cell EMT may also be important for recruiting other collagen-producing cells. We have developed a system to study lung epithelial cells in culture and determine if they release signaling molecules that can attract and activate other cells types potentially involved in fibrogenesis. In this way, lung epithelial cells may be critica in orchestrating the fibrotic process. Finally, we will study a family of transcription factors, the Helix- Loop-Helix (HLH) family that has been implicated in regulating EMT. Using combined animal model and cell culture approach we will be able to determine if these HLH factors regulate the ability of epithelial cells to produce collagen, signal to other cell types and regulae fibrosis. These studies will help define previously unexplored mechanisms that may regulate fibrosis with the potential of designing new and better therapies.

描述(申请人提供)：本申请的目标是明确不同类型的细胞，特别是肺上皮细胞在肺纤维化发展中的作用。进行性纤维化是许多慢性疾病的共同特征，导致显著的发病率和死亡率。在特发性肺纤维化(IPF)等疾病中，纤维化也可以在没有任何已知原因的情况下发生。IPF是一种毁灭性的疾病，全世界有500多万人受到影响。中位生存期为确诊后3-5年，目前的药物治疗很大程度上无效。尽管进行了密集的研究，但我们对调节纤维化的机制仍然知之甚少，甚至像哪些细胞产生富含胶原蛋白的疤痕这样的基本问题仍然没有答案。以前的工作主要集中在成纤维细胞的功能上。然而，一种新的范式正在出现，在这种范式中，上皮细胞的功能在决定纤维化形成的进展中起着关键作用。这种可能性是令人兴奋的，因为上皮细胞的作用尚未确定，更清楚地了解调节上皮细胞行为的机制有可能为更好的治疗干预提供新的靶点。在过去的几年里，我们已经开发了几种技术来确定肺上皮细胞在纤维化形成过程中的功能和调节。利用动物模型，我们和其他人发现，在纤维化形成过程中，上皮细胞能够在上皮-间充质转变(EMT)过程中转变为成纤维细胞样细胞。在EMT过程中，肺上皮细胞可能获得产生I型胶原的能力，I型胶原是纤维化瘢痕的主要成分。肺上皮细胞或任何其他细胞类型对胶原丰富的纤维化的贡献程度尚不清楚，我们已经培育了一只小鼠，我们可以在其中删除不同细胞类型中的I型胶原基因。因此，我们将能够确定哪种细胞类型(S)在纤维化形成过程中直接促进胶原合成。肺上皮细胞EMT对于招募其他胶原生成细胞也可能是重要的。我们已经开发了一种系统来研究培养中的肺上皮细胞，并确定它们是否释放信号分子来吸引和激活其他可能参与纤维化形成的细胞类型。在这种情况下，肺上皮细胞可能在纤维化过程中起关键作用。最后，我们将研究一个转录因子家族，即参与调节EMT的螺旋-环-螺旋(HLH)家族。利用动物模型和细胞培养相结合的方法，我们将能够确定这些HLH因子是否调节上皮细胞产生胶原的能力，向其他类型的细胞发出信号，以及调节纤维化。这些研究将有助于确定以前未探索过的可能调节纤维化的机制，并有可能设计出新的更好的治疗方法。