Identification of stage and cell specific cellular and gene regulatory networks involved in the progression of idiopathic pulmonary fibrosis

特发性肺纤维化（IPF）是人类肺部的一种进行性纤维化疾病，没有确定的病因。受IPF影响的个体往往会经历肺功能的进行性丧失，并伴有生活质量的严重下降，可用的治疗方案有限，而且没有一种能治愈。通常IPF患者的准确诊断是困难的，因为临床表现可能是可变的，分子诊断参数不存在。病理生理上IPF的特征是肺成纤维细胞对衰老气道上皮细胞指示的修复回路故障的反应，导致异常胶原沉积。衰老气道上皮细胞的清除和组织修复机制的协调是由组织驻留和招募的单核吞噬细胞严格调节的。因此，了解单核吞噬细胞在IPF进展和调控中的作用是至关重要的。为了揭示人类单核吞噬细胞在IPF的进展和分子病理中的作用，并评估其诊断潜力，我们建议研究轻度、中度或重度IPF患者的支气管肺泡免疫细胞区室。利用最先进的单细胞技术，如单细胞转录组学和高维流式细胞术，我们将评估疾病分期和细胞区室特异性分子网络，并确定纤维化进展和疾病严重程度的新决定因素，这些决定因素反过来将与临床参数联系起来，以帮助诊断。接下来，我们将选择具有最大预测潜力的分子，并将开发临床应用的流式细胞术方法，以预测疾病进展并提高分期特异性诊断。总的来说，该提案旨在以细胞类型特异性的方式确定IPF进展和严重程度的新分子决定因素，从而确定新的生物标志物和治疗靶点，从而个性化和改善IPF的治疗和诊断。

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing disorder of the human lung, with no causative factors identified. Individuals affected by IPF often undergo a progressive loss of lung function accompanied by a severe decline in the quality of life, with limited treatment of options available and none of them being curative. Often an accurate diagnosis of IPF patients is difficult as the clinical presentation can be variable and molecular diagnosis parameters do not exist. Pathophysiologically IPF is characterized by aberrant collagen deposition by pulmonary fibroblasts in response to malfunctioning repair circuits instructed by senescent airway epithelial cells. The clearance of senescent airway epithelial cells and orchestration of tissue repair mechanisms is tightly regulated by tissue-resident and recruited mononuclear phagocytes. Therefore it is crucial to understand the role of mononuclear phagocytes in the progression and regulation of IPF. To reveal the role of human mononuclear phagocytes for the progression and molecular pathology of IPF as well as to gauge their diagnostic potential, we propose to investigate the bronchoalveolar immune cell compartment of individuals diagnosed either with mild, moderate, or severe IPF. Utilizing state of the art single-cell technologies, such as single-cell transcriptomics and high dimensional flow cytometry we will assess the disease stage and cellular compartment-specific molecular networks and identify novel determinants of fibrosis progression and disease severity, which in turn will be linked to clinical parameters to aid diagnosis. Next, we will select the molecules which harbor the greatest predictive potential and will develop a clinically applicable flow cytometry approach in order to predict disease progression and to improve stage-specific diagnosis. Collectively this proposal aims to identify novel molecular determinants of IPF progression and severity in a cell type-specific manner, enabling identification of novel biomarkers and therapeutic targets to personalize and improve treatment and diagnosis of IPF.