矽肺由长期吸入游离二氧化硅粉尘引起，以矽结节和肺纤维化为主要病理特征，是我国发病率较高的法定职业病1；临床诊治目前主要面临早期无筛检诊断方法，后期肺纤维化无特效治疗手段这两大难题；而后期肺纤维化具有持续进展和不可逆的特点，多种细胞过度增殖迁移是矽肺纤维化的主要特征，失巢凋亡抵抗导致的细胞增殖失控可能是矽肺纤维化发生的主要机制。.环状RNA（circRNA）作为基因组中重要的“暗物质”，是合适的临床诊断标记物与疾病干预靶点。申请者前期研究发现，circRNA参与矽肺发生发展各过程，如成纤维细胞的增殖和内皮/上皮间质转化。基于以上结果，申请者提出“circRNA介导的失巢凋亡抵抗是矽肺纤维化发生发展的重要机制”假说，应用现代分子生物学和经典药理学方法，从整体、细胞和分子水平系统揭示circRNA与失巢凋亡抵抗在矽肺纤维化中的功能和作用机制，为临床治疗策略的选择和治疗药物靶标的遴选提供重要线索。

The inhalation of silicon dioxide particles causes an untreatable pulmonary disease, named as “silicosis”, characterized by progressive lung fibrosis and silicosis nodules， which is one of National occupational diseases with the high morbidity. While the primary cause of this often devastating disease remains elusive, diagnosis of silicosis could easily be missed, since which needs carefully documented records of occupational exposure and radiological features, with exclusion of other competing diagnoses. The late stage of silicosis is characterized by sustained and irreversible pulmonary fibrosis, in which many types of cell are involved, such as pulmonary fibroblasts (PFBs), alveolar epithelial cells (AECs), pulmonary microvascular epithelial cells (PMECs). The over-proliferation/migration of cell is main cause of pulmonary fibrosis which may due to the anoikis resistance...As a “dark matter” in genome, circular RNAs (circRNAs) are ubiquitous in molecular biology as a subclass of non-coding RNAs involved in many diseases served as transcription regulators or as sponges for small RNA regulators. Previous studies from our laboratory suggested that circRNA regulated alveolar macrophage activation, pulmonary fibroblast proliferation and epithelial/ epithelial cells Mesenchymal transition (EMT/EndMT). However, the detailed cellular and molecular mechanisms underlying fibrosis in response to silica remain unknown. Therefore, we hypothesized that circRNA-induced anoikis resistance mediated pulmonary fibrosis in silicosis. The proposed studies will be initiated by high throughput screening of tissue sample followed by study in intact animals as well as primary cell cultures. Studies using classic pharmacological methods will be combined with molecular biological techniques, as well as immunological methods, all of which are currently well established in our laboratory. This proposal is both novel and innovative in that the efficacy of regulation of circRNAs can be of value to prevent or halt progression of silicosis in people. Our study will decipher the link between circRNAs and anoikis resistance with subsequent pulmonary fibrosis induced by silica, providing a novel insight into the potential of circRNAs in terms of opening up novel therapeutic avenues for silicosis.