人类基因组中含有大量的长非编码RNA (LncRNA)，它们调控着细胞与机体的各种功能，并已有报道称LncRNA的表达异常与人类的疾病密切相关，但其具体调控机制还不清楚。TGF-β作为维持人类细胞稳态的重要因子，具有着广泛的生物学功能，其信号的传递主要通过Smad蛋白直接参与的转录调控。本课题计划结合高通量测序和功能筛选的方法，拟发现和鉴定可以与Smad蛋白相互作用的LncRNA-蛋白复合物，并深入阐述其生物学功能和分子机制，从而探索LncRNA-蛋白复合物特异性调控TGF-β/Smad信号转导的生理学和病理学意义。申请者在前期工作中已筛选出一个LncRNA-蛋白复合物，该复合物能够通过结合Smad3并促进了其的转录活性，从而上调TGF-信号通路。本研究将深入研究LncRNA-蛋白复合物参与调控TGF-β/Smad信号通路的具体分子机理，该研究将对癌症治疗，组织再生的研究都具有重大意义。

Abundant LncRNAs play critical roles in a wide variety of cellular processes and biological functions and its abnormal expression contributes to development of human diseases. However, how LncRNA regulates gene expression and cellular functions remains elusive. Transforming growth factor-beta (TGF-β) superfamily controls diverse developmental processes and the pathogenesis of many diseases, including cancer and fibrotic diseases. As key TGF-β signal transducers and transcription factors, Smads orchestrate the transcription of specific gene networks and ultimatetly control a broad range of cellular functions in response to TGF-β. In this project, we use a combinatorial approach of high-throughput RNA sequencing and functional screen to identify novel LncRNA-Protein complex (LncRNP) in controlling TGF-β/Smad signal transduction. In our preliminary studies, we discovered that a LncRNP complex binds to and enhances Smad3 transcriptional activity, thereby promoting TGF-β signaling and physiological responses. Our proposed studies will not only elucidate new molecular mechanisms for LncRNP-dependent regulation of TGF-β signal transduction, but also provide a foundation for gaining insights into tumor formation and metastasis.