气球样变肝细胞发生发展在非酒精性脂肪性肝病自然史肝脏组织稳态维持中的作用及其机制研究

非酒精性脂肪性肝病（NAFLD）已成为全球范围日益严重的肝病负担，需要更多的创新性基础发现引导相关无创诊断和干预治疗的研发。在多种组织学特征参数中，气球样变肝细胞（BH）在诊断非酒精性脂肪性肝炎（NASH）和评估预后方面具有重要临床价值，但是关于BH发生演变及其调控机制，目前仍缺乏系统清晰的认知。在相关理论分析、系统文献回顾和前期实验发现的基础上，本项目提出：BH发生可能是NAFLD肝组织稳态维持作用中的一种保护性细胞反应，拟采用单细胞分析技术结合形态学和功能学验证等实验手段，在体内外疾病模型中系统动态地观察BH与脂肪变肝细胞和正常肝细胞之间表型特征的变化关系以及其主要调控通路和调控特点，并观察直接干预BH发生对NAFLD肝组织损伤进展的影响。本项目研究内容将为了解BH发生演变及其基础机制提供重要线索，有助于发现NAFLD肝组织代偿机制的新思路，并为推进NASH诊疗研发提供新靶点。

Nonalcoholic fatty liver disease (NAFLD) is a growing global health burden. Innovative basic study is highly valued in terms of accelerating the efficient development of diagnostic tools and therapeutic drugs. Among all the histologic features, the presence of ballooning hepatocytes (BHs) is fundamentally important for the definitive diagnosis of NASH and evaluating therapeutic effects. However, regarding what the BHs come from and what are the underlying mechanisms, there have yet to be any clear answers. On the basis of theoretical reasoning, literatures review, and interpretation of data from our pilot study, we propose that BH formation can be a protective cellular response which is withstanding the effect of liver tissue homeostasis maintenance in the scenario of NAFLD. By the means of single-cell resolution analysis and further validation in morphological and functional tests, we will perform a systematic, longitudinal observation of both in vitro and in vivo models on issues including, the structural and functional phenotypic features of BH, steatosis hepatocyte, and normal hepatocyte, the differences and interactions between these features, the major regulatory pathways underlying, and the pattern of regulation incidence. We also will test if interruption of BH formation could have any effects on the progression of NAFLD liver injury. Our data can be substantially helpful to get clear clue on how BHs are generated and what it means to the natural history of NAFLD. These can be important complementary information to current NAFLD pathophysiology as well as can provide more targets for the research of NASH diagnosis and treatment.