截短型转化生长因子βⅡ型受体多肽的筛选和抗肝纤维化作用研究

Liver fibrosis, a major cause of the morbidity and mortality of chronic liver disease, disrupts the normal architecture of the liver and leads to liver failure. Transforming growth factor-β1 (TGF-β1) is considered as a major profibrogenic cytokine and a potent inducer of liver fibrosis. It is confirmed that blocking TGF-β1-mediated signaling pathways is effective to attenuate TGF-β1-induced fibrosis. Transforming growth factor-beta receptor type II (TβRII) plays an important role in TGF-β1-mediated signaling pathways. Therefore, in the study, the applicant proposes the hypothesis: novel truncated TβRII peptides (tTβRII) that potentially interact with TGF-β1 will be successfully screened to confirm whether novel tTβRII peptides could compete with the wild-type TβRII (wtTβRII) by bioinformatics and biotechnology. Next, the effects of recombinant Tat-tTβRII on TGF-β1-induced LX-2 and HSC-T6 cells will be used to confirm whether novel tTβRII peptides could attenuate the function of excessive TGF-β1 in the process of fibrosis. We further to investigate the effects of Tat-tTβRII on carbon tetrachloride (CCl4) -induced liver fibrosis animal model. Thus, it may provide a new strategy for preventing the development of fibrosis.

肝纤维化是导致慢性肝功能衰竭的主要原因，已成为危害人体健康的主要疾病。在组织纤维化发生发展过程中，转化生长因子-β1 (TGF-β1)发挥了关键的作用，阻断TGF-β1信号转导通路，被证实能有效抑制TGF-β1过表达所引发的组织纤维化。而在TGF-β1信号转导通路中，转化生长因子βII型受体（TβRII）处于核心地位，因此，本研究拟以TβRII为靶标，通过生物信息学和生物技术手段筛选更为“高效”的截短型TβRII多肽（tTβRII）。通过中试制备Tat-tTβRII来验证其是否能与胞内野生型的TβRII竞争结合TGF-β1并探查该多肽对TGF-β1诱导的人肝星状细胞（LX-2）和大鼠肝星状细胞（HSC-T6）影响，验证其能否“高效”弱化过量TGF-β1引起的纤维化；并依托四氯化碳（CCl4）诱导的SD大鼠肝纤维化模型，验证该多肽对其保护作用，为相应的纤维化疾病的防治提供研究基础。

肝纤维化是导致慢性肝功能衰竭的主要原因，已成为危害人体健康的主要疾病。阻断TGF-β1信号转导通路，被证实能有效抑制TGF-β1过表达所引发的组织纤维化。本研究通过筛选截短型转化生长因子βII型受体（TβRII），进而拮抗野生型TβRII与TGF-β1结合来达到抑制纤维化相关基因表达，为抗纤维化药物开发提供可能。本研究实验结果表明，筛选的截短型TβRII不仅能抑制TGF-β1诱导的肝星状细胞的增殖和纤维化相关基因的表达，而且还可通过抑制TGFβ1/SMAD信号通路来缓解四氯化碳（CCl4）诱导肝纤维化动物模型；同时筛选的截短型TβRII还能抑制TGF-β1诱导的肾小管上皮细胞纤维化和单侧输尿管梗阻（UUO）诱导的小鼠肾纤维化。以上结果表明，截短型TβRII对纤维化肝脏和肾脏均起到保护作用，为相应的纤维化疾病的防治提供研究基础。