XBP1 mRNA剪切抑制剂发现及其抗非酒精性脂肪性肝病的作用与机制研究

Non-alcoholic fatty liver disease is one of the world's most important public health problems, and also has been attached great importance as the chronic liver disease in China. There is no standardized treatment protocols, drug development of safe and effective treatment of NAFLD is particularly urgent and of great significance. XBP1s plays an important role in the two-hit hypothesis of NAFLD pathogenesis. Furthermore, XBP1 splicing is active in many fatty liver mice models, but still no XBP1s inhibitors against NAFLD was reported. Therefore, we propose a scientific hypothesis: Discovering XBP1s small molecule inhibitors with chemical biology strategy may have a role in the treatment of fatty liver. So, we wish to design and establish Cell based screening model targeting the XBP1 splicing, to find novel XBP1 splicing inhibitors through high-throughput screening, to study the regulatory mechanism of XBP1 mRNA splicing, to evaluate the ability against fatty liver disease using high-fructose and high-fat induced fatty liver mouse models. All the work would lay the foundation for new research strategies and lead compounds for the fatty liver drug discovery.

非酒精性脂肪性肝病（NAFLD）是全球最重要的公共健康问题之一，也是我国近年非常重视的慢性肝病。但目前尚无标准化治疗方案, 有效治疗NAFLD的药物开发显得尤为迫切与意义重大。XBP1s在NAFLD的发病机制二次打击病因学说的关键环节都起着非常重要的生理作用，而且XBP1s在多个脂肪肝小鼠动物肝脏模型中处于激活高表达状态，但尚没有XBP1s抑制剂用于NAFLD治疗的研究报道。所以我们提出一个科学假设：应用化学生物学手段发现XBP1S的小分子抑制剂可能具有缓解和治疗NAFLD的作用。基于科学假设，本项目设计建立细胞水平的XBP1剪切抑制剂筛选模型，通过高通量筛选发现结构多样新颖的XBP1剪切抑制剂，研究XBP1 mRNA剪切调控机制，并分别在高果糖和高脂肪诱导的脂肪肝小鼠动物模型上评价其改善脂肪肝能力，为开发有效调控NAFLD药物提供新研究策略,并提供靶向XBP1s的抗NAFLD先导化合物。

XBP1s 在多个脂肪肝小鼠动物肝脏模型中处于激活高表达状态，但尚没有XBP1s 抑制剂用于相关脂代谢调控的研究报道。所以我们提出一个科学假设：应用化学生物学手段发现XBP1S 的小分子抑制剂可能具有缓解和治疗脂代谢紊乱的作用。通过本项目的4年工作，我们建立一套细胞与分子水平的XBP1 剪切抑制剂筛选模型，通过高通量筛选发现结构多样新颖的XBP1 剪切抑制剂，并在细胞水平以及高脂肪诱导的小鼠动物模型上评价其改善脂肪代谢异常的能力，从中发现多个化合物在细胞水平对脂肪细胞分化以及肝细胞脂质合成均具有抑制作用，其中嘧菌酯在整体动物水平体现出显著的提高胰岛素敏感性和降低肝脏脂肪和血脂效果。目前的结果为未来进一步开发有效调控NAFLD 药物提供新研究策略,并提供靶向XBP1s 的抗NAFLD 先导化合物。