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: 8469897
• 负责人: KEVIN KEEWOUN KIM
• 金额: $ 37.01万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469897
• 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（由申请人提供）：本申请的目的是确定不同细胞类型，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，导致显着的发病和死亡。特发性肺纤维化 (IPF) 等疾病也可能在没有任何已知原因的情况下发生纤维化。 IPF 是一种毁灭性疾病，影响全球超过 500 万人。从诊断之日起，中位生存期为 3-5 年，目前的药物治疗基本上无效。尽管进行了大量的研究，但我们对调节纤维化的机制仍然知之甚少，甚至诸如哪些细胞产生富含胶原蛋白的疤痕等基本问题仍未得到解答。先前的工作主要集中于成纤维细胞的功能。然而，一种新的范例正在出现，其中上皮细胞的功能在决定纤维发生的进展中发挥着关键作用。这种可能性令人兴奋，因为上皮细胞的作用尚不清楚，对调节上皮细胞行为的机制有更清晰的了解，有可能为更好的治疗干预提供新的靶点。在过去几年中，我们开发了多种技术来定义肺上皮细胞在纤维发生过程中的功能和调节。我们和其他人使用动物模型发现，在纤维发生过程中，上皮细胞能够在上皮间质转化（EMT）过程中转化为成纤维细胞样细胞。在 EMT 期间，肺上皮细胞可能获得产生 I 型胶原的能力，I 型胶原是纤维化疤痕的主要成分。肺上皮细胞或任何其他细胞类型对富含胶原蛋白的纤维化的贡献程度仍然未知，我们已经培育出一种小鼠，可以在其中删除不同细胞类型中的 I 型胶原蛋白基因。因此，我们将能够明确确定哪些细胞类型在纤维发生过程中直接促进胶原蛋白合成。肺上皮细胞 EMT 对于招募其他胶原蛋白生成细胞也可能很重要。我们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可以吸引和激活可能参与纤维形成的其他细胞类型的信号分子。通过这种方式，肺上皮细胞可能在协调纤维化过程中发挥关键作用。最后，我们将研究一个转录因子家族，即与调节 EMT 相关的螺旋-环-螺旋 (HLH) 家族。通过结合动物模型和细胞培养方法，我们将能够确定这些 HLH 因子是否调节上皮细胞产生胶原蛋白、向其他细胞类型发出信号和调节纤维化的能力。这些研究将有助于定义以前未探索过的调节纤维化的机制，并有可能设计出新的更好的疗法。