Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis

项目总结 特发性肺纤维化(IPF)是一种致命的纤维性肺部疾病，由于 成纤维细胞活化，并形成瘢痕组织。大约有13万美国人患有IPF，其中 据估计，每年新诊断的病例有5万例。尽管人们普遍认为肌成纤维细胞 积聚是特发性肺间质纤维化发病机制的中心组成部分，它是转录程序(S)协调的 成纤维细胞的活化包括成纤维细胞向肌成纤维细胞的转化、存活、迁移和细胞外基质 组织的定义不明确，代表着该领域的重大知识差距。Sox9是 HMG-box转录因子家族，由上皮祖细胞选择性表达以调节 肺的分支形态发生和作为软骨形成一部分的胶原的有组织沉积 多个器官。然而，在成人纤维化肺中，sox9在成纤维细胞活化中的作用研究甚少。 疾病。我们的新发现确定了SOX9在IPF和IPF的肺间充质细胞中表达上调 作为FMT、肌成纤维细胞存活、迁移和细胞外基质产生的正向调节因子。损失的损失 SOX9表达抑制间充质细胞α-SMA表达和肌成纤维细胞转化 分别取肺组织和转化生长因子α模型。作为支持，最近发表的一项研究表明，Sox9在 慢性肝病患者与纤维化严重程度和进展为肝硬变相关。 综上所述，这些发现使我们假设Sox9对FMT起着积极的调节作用， 肺纤维化发病机制中肌成纤维细胞的存活、迁移和细胞外基质。在这项研究中， 我们提出了三个具体目标：1)确定Sox9诱导成纤维细胞活化的机制；2) 在体内建立表达Sox9的间充质细胞在肺纤维化发病机制中的作用； 3)确定Sox9促进肌成纤维细胞存活和进展的机制 持续的肺纤维化。我们将使用先进的分子方法和小鼠转基因方法， 再加上在体内和体外对Sox9驱动的这些过程的详细生化分析。完成 拟议的实验可能会使人们对Sox9驱动的成纤维细胞激活有重要的了解。 多学科团队将促进及时的方法与专业知识的所有方面的肺部病理和 支持IPF未来的翻译研究。我们的方法是创新的，因为产生了新的转基因 小鼠检测Sox9在肺纤维化中的间质细胞特异性功能。拟议的研究是 重要是这项研究的完成将增加对导致成纤维细胞的机制的理解 IPF的激活，这反过来将导致治疗的先进医学疗法和可能的治愈或 预防这种使人衰弱的肺病。

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is incurable and progressive due to fibroblast activation, and the formation of scar tissue. Approximately 130,000 Americans suffer from IPF, with an estimated 50,000 new cases diagnosed each year. Although it is well accepted that myofibroblast accumulation is a central component of pathogenesis in IPF, the transcriptional program(s) that orchestrate fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), survival, migration and ECM organization are poorly defined and represent a significant knowledge gap in the field. Sox9 is a member of the HMG-box family of transcription factors that are selectively expressed by epithelial progenitor cells to modulate branching morphogenesis in the lung and the organized deposition of collagen as part of cartilage formation in multiple organs. However, the role of Sox9 in fibroblast activation has been poorly studied in adult fibrotic lung diseases. Our new findings have determined that Sox9 is upregulated in lung mesenchymal cells of IPF and functions as a positive regulator of FMT, myofibroblast survival, migration and ECM production. The loss of Sox9 expression has attenuated αSMA expression and myofibroblast transformation in mesenchymal cells isolated from IPF lungs and TGFα model. In support, a recent published study suggest Sox9 upregulation in patients with chronic liver disease that correlated with fibrosis severity and progression towards cirrhosis. Taken together, these findings lead us to postulate that Sox9 functions as a positive regulator of FMT, myofibroblast survival, migration, and ECM in the pathogenesis of pulmonary fibrosis. For this study, we propose three specific aims: 1) determine mechanisms by which Sox9 induces fibroblast activation; 2) establish in vivo the role of Sox9-expressing mesenchymal cells in the pathogenesis of pulmonary fibrosis; and 3) identify mechanisms by which Sox9 augments myofibroblast survival and the progression of established and ongoing pulmonary fibrosis. We will use advanced molecular methods and mouse transgenic approaches, coupled with detailed biochemical analysis of these Sox9-driven processes in vivo and in vitro. Completion of the proposed experiments is likely to impart a significant understanding of Sox9-driven fibroblast activation. The multidisciplinary team will facilitate a timely approach with expertise in all aspects of lung pathology and support future translational studies in IPF. Our approach is innovative due to the generation of novel transgenic mice to test mesenchymal cell-specific functions of Sox9 in pulmonary fibrosis. The proposed research is significant in that completion of this study will increase an understanding of the mechanisms causing fibroblast activation in IPF, which in turn will lead to advanced medical therapies for the treatment and possible cure or prevention of this debilitating lung disease.