矽肺是吸入含二氧化硅粉尘颗粒，在人肺内沉积后引发的一种尚无特效治疗措施的肺部疾病，其特征是疾病早期的肺部炎症和后期进行性肺纤维化。矽肺诊治面临早期缺少筛检诊断方法，后期肺纤维化缺乏特效治疗措施。环状RNA（circRNA）是调控生命活动重要的非编码RNA，由于circRNA比线性RNA更稳定，因此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，锌指蛋白家族参与了矽肺发生发展过程；circRNA高通量筛选结果发现，调控锌指蛋白家族成员ZC3H4的ciR-0001544参与矽肺炎性反应和纤维化进程。基于以上结果，申请者提出“ciR-0001544靶向调控ZC3H4是矽肺诊治的有效和关键靶点”假说，拟应用分子生物学手段，结合经典药理学方法，从整体、细胞和分子水平系统揭示此通路在矽肺炎症和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 pneumoconiosis, an untreatable pulmonary disease characterized by alveolar inflammation at the early stage and progressive lung fibrosis at the late stage. Although more and more studies were undertaken to dissect the pathological mechanisms underlying the process of silicosis, 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. As yet, no curative treatment exists, but comprehensive management strategies help to improve quality of life and slow deterioration. Thus, further efforts are needed to find early molecular marker of diagnosis, new target to control the fibrosis induced by silica.. Circular RNAs are ubiquitous in molecular biology. Recent papers have described the presence of circular RNA species from back-spliced exons in mammals (circular exonic RNAs, circRNAs) and have established that they are very abundant and are differentially expressed Circular RNAs may, for example, serve as transcription regulators or as sponges for small RNA regulators. . Our previous studies also suggested that monocyte chemotactic protein 1 (MCP-1) induced protein 1 (MCPIP1, ZC3H12A), an important member of zinc finger protein family, played a critical role in fibroblast proliferation and migration. However, the detailed cellular and molecular mechanisms underlying inflammation and the subsequent fibrosis in response to silica remain unknown. Circular RNA microarray assay suggested that ciR-0001544 level in mouse lung exposure to SiO2 was increased. Interestingly, ciR-0001544 is the regulator of ZC3H4, another important member of zinc finger protein family. Moreover, micro RNA microarray assay found that miR-212 was also decreased, which can inhibit the expression of ZC3H4. . Therefore, we hypothesized that ciR-0001544 targeting regulation of ZC3H4 will be the potential target of curative treatment for silicosis involving in regulation of inflammation and fibrosis. The proposed studies will be initiated in human 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 ciR-0001544/ZC3H4 can be of value to prevent or halt progression of silicosis in people. Our study will decipher the link between ciR-0001544/ZC3H4 and inflammation with subsequent fibrosis, induced by silica providing a novel insight into the potential of ciR-0001544/ZC3H4 in terms of opening up novel therapeutic avenues for silicosis.