清道夫受体A（SRA，又称Msr1）是主要表达于髓系细胞的天然免疫分子。我们前期研究表明SRA在维持肝脏免疫稳态中发挥重要作用。最近发现，酒精性肝病（ALD）模型小鼠肝内巨噬细胞（MΦ）SRA表达上调；与WT小鼠相比，SRA-/-小鼠酒精性肝损伤加剧、肝内MΦ线粒体损伤严重且Notch通路活化增强。据此提出假说：SRA通过Notch信号通路影响MΦ功能进而调节ALD病变。拟开展以下研究：①动物：利用WT和SRA-/-小鼠建立ALD模型，研究SRA、Notch通路及MΦ功能相互关联及其与ALD病变的关系；②体外：SRA调控Notch通路的机制；③临床：SRA与Notch通路及ALD病变的关系。研究将揭示SRA水平—Notch通路活化—MΦ功能—ALD病变的关系，为深入理解ALD的发病机制和Notch信号通路的调控增添新内容，并为靶向SRA调节MΦ功能以治疗ALD及相关炎症性疾病提供实验依据。

Scavenger receptor A (SRA), also known as macrophage scavenger receptor 1 (Msr1), is an important innate immune molecule which preferentially expressed on myeloid cells. Our previous studies have demonstrated SRA is a key regulator of liver homeostasis. Recently, we observed that SRA is highly up-regulated in the livers of mice with alcoholic liver disease (ALD). Strikingly, genetic SRA ablation strongly sensitizes mice to alcohol-induced liver injury. SRA loss increased liver pathology correlated with heavy hepatic macrophage mitochondrial damage and heightened activation of Notch signaling pathway. On the basis of these findings, we propose the present grant. The regulation mechanism of SRA on the activation of Notch signaling pathway and its influences on macrophage metabolism and function will be studied. Alcohol-induced liver injury, inflammation, hepatic macrophage function and Notch signaling pathway activation were compared between wild-type and SRA deficient mice. The effects of SRA on the initiation and activation of Notch pathway as well as the underlying mechanisms will be investigated in vitro. Human liver tissues and blood from patients with ALD and healthy participants will be collected. The activation of Notch pathway, as well as the level of SRA in hepatic macrophages and peripheral blood mononuclear cells will be examined, and the association among SRA levels, Notch pathway and disease severity will be analyzed. The study will elucidate the relationship among SRA levels, Notch pathway activation, macrophage function, and the pathogenesis of ALD, which provides a new understanding about the development of ALD and regulation of Notch pathway activation. Most importantly, this study will substantiate the concept that SRA is a vital regulator of liver homeostasis, thus making it a potential target for modulation in the clinical settings of alcohol and other risk factors-caused liver damage.