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; 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）：本应用的目的是定义不同细胞类型的作用，尤其是肺上皮细胞在发育肺纤维化中的作用。进行性纤维化是许多导致明显发病和死亡的许多慢性疾病的共同特征。在没有任何已知原因的疾病（例如特发性肺纤维化（IPF））中，纤维化也可能发生。 IPF是一种毁灭性的疾病，在全球范围内影响超过500万人。自诊断后的中位生存期为3 - 5年，当前的医疗疗法在很大程度上无效。尽管进行了激烈的调查，但我们仍然对调节纤维化的机制，甚至基本问题（例如哪些细胞产生富含胶原蛋白的疤痕）仍然没有任何了解。先前的工作主要集中在成纤维细胞的功能上。然而，新的范式正在出现，其中上皮细胞的功能在确定纤维发生的进展中起着关键作用。这种可能性令人兴奋，因为上皮细胞的作用是不确定的，并且对调节上皮细胞行为的机制有更清晰的理解，具有为更好的治疗干预提供新靶标。在过去的几年中，我们开发了几种技术来定义纤维化过程中肺上皮细胞的功能和调节。使用动物模型，我们和其他人发现，在纤维发生过程中，上皮细胞能够在上皮 - 间质转变（EMT）的过程中转变为成纤维细胞样细胞。在EMT期间，肺上皮细胞可能会获得产生I型胶原蛋白的能力，I型胶原蛋白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有助于富含胶原蛋白的纤维化的程度尚不清楚，并且我们产生了一只小鼠，在该小鼠中我们可以在不同的细胞类型中删除I型胶原基因。因此，我们将能够确定确定哪种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对于募集其他产生胶原蛋白的细胞也可能很重要。我们已经开发了一种研究培养中肺上皮细胞的系统，并确定它们是否释放了可以吸引和激活潜在参与纤维发生的其他细胞类型的信号分子。通过这种方式，肺上皮细胞可能是依靠纤维化过程的批评。最后，我们将研究一个与调节EMT有关的转录因子家族，即螺旋环螺旋（HLH）家族。使用联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的能力，向其他细胞类型发信号和调节纤维化。这些研究将有助于定义以前未开发的机制，这些机制可能会通过设计新的和更好的疗法来调节纤维化。