髓系细胞在衰老加重酒精性肝病进程中的作用以及天然杀伤(NK)/NKT细胞的调节机制

The dramatic increase of the aging population and alcohol abuse in China have already become a huge healthcare challenges to exacerbate the development and progression of alcoholic liver disease (ALD). Our previous work shows that aging exacerbates alcoholic liver injury and fibrosis in mice through the downregulation of SIRT1 in hepatocytes and hepatic stellate cells. Inflammation plays a crucial role in the pathogenesis of ALD. We hypothesize that myeloid cell play an important role in aging exacerbating the progression of ALD. The reduciton of SIRT1 in myeloid cell during aging causes the enhanced inflammation and natural kill (NK) /NKT cell regulates inflammaion and injury through killing target cells and secreting cytokines. To test this hypothesis, Myeloid cell SIRT1 deficient mice will be used to compare the phenotype difference with that in wild-type control mice by alcohol liver injury and fibrosis animal models. Next we plan to use in vitro experiments to investigate how SIRT1 in myeloid cells regulate inflammation through transcript factor NF-κB/STAT3. The effects of NK/NKT cells on the progression of ALD through target cells killing and cytokine production will also be investigated in vitro and in vivo. Last, the results from animal experiments will be confirmed in human study. This proposal may clarify the myeloid cell function in aging exacerbates the development and progression of ALD and the regulatory roles of NK/NKT cells. This project also may provide some evidence to developing a new therapeutic strategy in ALD through targeting SIRT1 and immnue cells.

人口老龄化及酒精的大量饮用是促进中国酒精性肝病(ALD)发病进展的重要原因。前期发现衰老可以加重小鼠酒精性肝损伤和肝纤维化，其机制与衰老过程中肝细胞和肝星状细胞上SIRT1表达下降有关。炎症在ALD发病中发挥核心作用。我们推测髓系细胞在衰老加重ALD的进程中发挥重要作用，衰老时髓系细胞SIRT1下降可导致炎症增加，而天然杀伤(NK)/NKT细胞可通过靶向杀伤和分泌细胞因子发挥间接调节作用。本课题拟应用髓系细胞特异性SIRT1敲除小鼠，比较年轻和中老年小鼠在酒精刺激下的表型差异；体外验证髓系细胞SIRT1可通过NF-κB/STAT3调节炎症反应，体内外研究NK/NKT通过杀伤作用和细胞因子影响炎症和ALD的进展；最后将上述动物研究结果进行临床类似性验证。本课题将进一步阐明髓系细胞在衰老加重ALD进展中的作用及NK/NKT细胞的调节功能，也为以SIRT1和免疫细胞为靶点治疗ALD提供实验依据。

人口老龄化及酒精的大量饮用是促进中国酒精性肝病(ALD)发病进展的重要原因。课题组发现衰老可以加重小鼠酒精性肝损伤和肝纤维化，其机制与衰老过程中肝细胞和肝星状细胞上SIRT1表达下降有关。我们后续研究了髓系细胞在衰老加重ALD的进程中发挥重要作用，发现衰老可通过影响中性粒细胞进SIRT1-miR-223轴而促进ALD进展。本课题阐明了衰老加重ALD进展中的作用，也为以SIRT1和免疫细胞为靶点治疗ALD提供实验依据。