A systems medicine approach to assessing functional metabolic changes during the development and progression of liver cirrhosis

评估肝硬化发生和进展过程中功能代谢变化的系统医学方法

• 批准号: 534075507
• 负责人: Privatdozent Dr. Nikolaus Berndt
• 金额: --
• 依托单位: Sektion Hepatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/534075507?language=en
• 关键词: systems; medicine; approach; assessing; functional

Non-alcoholic steatohepatitis (NASH) is about to become the most common cause of chronic liver disease in the western world. NASH usually starts with the accumulation of fat (triglycerides) in the liver, which progresses to a chronic inflammatory state with varying degrees of fibrosis in about 20% of all cases, potentially ending up in cirrhosis and severe liver failure. Notably, the liver can maintain its multiple metabolic functions over a long period of NASH progression. This remarkable metabolic reserve capacity of the liver is due to an up-regulation of metabolic capacities in the permanently shrinking fraction of hepatocytes. Metabolic dysfunction of the liver associated with clinical symptoms like jaundice, ascites, or neurological disorders will occur if this compensation collapses, and increased metabolic competence on the cellular level cannot compensate for the drop in supply of nutrients and oxygen due to structural changes of the liver tissue. Better understanding this intriguing interplay between structural and functional changes of the liver during NASH progression is the objective of this project. We will assess how cellular and structural changes behave in realistic liver fibrosis mouse models and evaluate how they translate into the human situation. By combining systems biochemistry, functional assays, and computational modeling, we will explore and delineate how the cellular and structural changes affect the short- and long-term regulation of hepatic central metabolism, including carbohydrate metabolism, lipid metabolism, amino acid metabolism, and ammonia and alcohol detoxification. From liver samples, we will generate protein abundance data by mass spectrometry and structural parameters from histology to generate individualized liver models on the cellular and tissue level. We will use these models to evaluate liver metabolism and use functional biochemical assays for validation. From our preliminary data, we suspect that structural changes hindering proper liver function will be, in part, compensated by metabolic adjustments occurring in individual hepatocytes. Only when a critical point is reached, and cellular compensation of structural deterioration is not possible anymore, do the clinical symptoms occur. We aim to rate at what stage a specific liver is in before reaching this critical point. We will apply our procedure to human liver specimens of different stages of liver fibrosis and cirrhosis from patients undergoing liver surgery. We will compare the proteomic and structural fingerprints, as well as the functional liver states between the different clinical groups (degree of fibrosis, steatosis, and inflammation) with the different stages of the animal models to investigate the transferability of the animal model to the human situation.

非酒精性脂肪性肝炎（NASH）即将成为西方世界慢性肝病的最常见原因。NASH通常始于肝脏中脂肪（甘油三酯）的积累，在约20%的所有病例中进展为慢性炎症状态，伴有不同程度的纤维化，最终可能导致肝硬化和严重肝功能衰竭。值得注意的是，肝脏可以在NASH进展的长时间内维持其多种代谢功能。肝脏这种显著的代谢储备能力是由于肝细胞永久萎缩部分的代谢能力上调。如果这种补偿崩溃，将发生与黄疸、腹水或神经系统疾病等临床症状相关的肝脏代谢功能障碍，并且细胞水平上代谢能力的增加不能补偿由于肝脏组织结构变化而导致的营养和氧气供应的下降。更好地理解NASH进展过程中肝脏结构和功能变化之间的这种有趣的相互作用是该项目的目标。我们将评估细胞和结构变化如何在现实的肝纤维化小鼠模型中表现，并评估它们如何转化为人类情况。通过结合系统生物化学，功能测定和计算建模，我们将探索和描述细胞和结构的变化如何影响肝脏中枢代谢的短期和长期调节，包括碳水化合物代谢，脂质代谢，氨基酸代谢，氨和酒精解毒。 从肝脏样本中，我们将通过质谱法和组织学结构参数生成蛋白质丰度数据，以在细胞和组织水平上生成个性化的肝脏模型。我们将使用这些模型来评估肝脏代谢，并使用功能生化检测进行验证。根据我们的初步数据，我们怀疑阻碍正常肝功能的结构变化将部分地通过个体肝细胞中发生的代谢调节来补偿。只有当达到一个临界点，并且结构退化的细胞补偿不再可能时，才会出现临床症状。我们的目标是在达到这个临界点之前，评估特定肝脏处于什么阶段。我们将把我们的方法应用于来自接受肝脏手术的患者的不同阶段的肝纤维化和肝硬化的人类肝脏标本。我们将比较蛋白质组和结构指纹，以及不同临床组（纤维化程度，脂肪变性和炎症）与动物模型不同阶段之间的功能性肝脏状态，以研究动物模型对人类情况的可转移性。