Function of epithelial-mesenchymal transition during pulmonary fibrosis

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，导致显著的发病率和死亡。纤维化也可以在诸如特发性肺纤维化（IPF）的疾病中在没有任何已知原因的情况下发生。IPF是一种破坏性疾病，影响全球超过500万人。中位生存期为3 - 5年，从诊断开始，目前的药物治疗在很大程度上无效。尽管进行了大量的研究，但我们对调节纤维化的机制仍然缺乏了解，甚至根本的问题，如哪些细胞产生富含胶原蛋白的瘢痕仍然没有答案。之前的工作主要集中在成纤维细胞的功能上。然而，一个新的范例正在出现，其中上皮细胞的功能在决定纤维化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是不确定的，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过程中的功能和调节。使用动物模型，我们和其他人已经发现，在纤维发生过程中，上皮细胞能够在上皮-间充质转化（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富含胶原蛋白的纤维化的贡献程度仍然未知，并且我们已经产生了一种小鼠，其中我们可以删除不同细胞类型中的I型胶原蛋白基因。因此，我们将能够明确地确定哪些细胞类型直接有助于纤维形成期间的胶原蛋白合成。肺上皮细胞EMT对于募集其他胶原蛋白产生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，这些信号分子可以吸引和激活可能参与纤维化的其他细胞类型。以这种方式，肺上皮细胞可能在协调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HLH家族，该家族参与调节EMT。使用组合的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，向其他细胞类型发出信号并调节纤维化。这些研究将有助于确定以前未探索的可能调节纤维化的机制，并有可能设计新的更好的治疗方法。

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.