P1 - Metabolic profiling of the hepatic sinusoid

P1 - 肝窦的代谢分析

• 批准号: 447239481
• 负责人: Professor Dr. Bruno Christ
• 金额: --
• 依托单位: Forschungslaboratorien der Chirurgischen Kliniken I und II
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/447239481?language=en
• 关键词: P1; Metabolic; profiling; hepatic; sinusoid

The comprehensive aim of the Research Unit “QualiPerF” is to compile a computational model encompassing the quantitative relationship between liver perfusion and metabolic functions in the context of liver surgery. In the long-term range this will support surgical planning and risk stratification. It may be assumed that liver surgery-induced perfusion perturbation may impact on hepatic metabolic functions. However, global function may not reflect the situation on the cellular level, since metabolic pathways are heterogeneously distributed in the liver parenchyma in a zonal pattern along the hepatic sinusoids. Therefore, the understanding of liver function on the organ level requires the understanding on the cellular level to establish a multi-scale computational model for the prediction of surgery-induced perfusion and function changes. Yet, while metabolic zonation per se is well documented, the quantitative relationship between perfusion changes and metabolic control on the sinusoidal level and their mutual interactions are unknown so far. We hypothesize that metabolic functions of the hepatocytes ultimately depend on the mitochondrial oxidative capacity providing energy for post-surgery organ regeneration. Yet, mitochondrial function may be exhausted by threshold perfusion restrictions, eventually causing hepatocyte dysfunction and metabolic impairment.Our project “Metabolic profiling of the hepatic sinusoid” aims to correlate steatosis- and surgery-induced changes in liver perfusion with changes of hepatocyte metabolic control coupled to mitochondrial function on the sinusoidal level in the rat model. We will provide as yet unknown quantitative data on the zonal distribution and dynamics of carbohydrate and lipid metabolism regulated by perfusion changes as induced by lipid overload and liver surgery. Further, we will define as yet unknown zonal mitochondrial activity as a function of carbohydrate and lipid metabolism, and identify mitochondrial dysfunction induced by flow restrictions as a potential pathomechanism in post-surgery liver failure. Finally, we will provide quantitative data for input into models of simulation of carbohydrate and lipid metabolism on the tissue and cellular scale. Thus, the project contributes data for computational modelling in joint projects of the Research Unit on the tissue and cellular level, and supports elucidation of biological mechanisms of perfusion control of metabolic zonation in the context of liver surgery. Mutual iterative interactions of the projects in the Research Unit will support model validation and textual refinement of experiments in order to improve model predictions as well as experimental strategies.

“QualiPerF”研究单位的综合目标是编制一个计算模型，涵盖肝脏手术中肝脏灌注和代谢功能之间的定量关系。从长远来看，这将支持手术计划和风险分层。可以假设肝脏手术引起的灌注扰动可能影响肝脏代谢功能。然而，整体功能可能无法反映细胞水平上的情况，因为代谢途径沿着肝窦以带状模式不均匀地分布在肝实质中。因此，在器官水平上理解肝功能需要在细胞水平上理解，以建立多尺度计算模型来预测手术引起的灌注和功能变化。然而，虽然代谢分区本身已有充分记录，但灌注变化和正弦水平代谢控制之间的定量关系以及它们之间的相互作用迄今为止尚不清楚。我们假设肝细胞的代谢功能最终取决于线粒体氧化能力，为术后器官再生提供能量。然而，线粒体功能可能会因阈值灌注限制而耗尽，最终导致肝细胞功能障碍和代谢损伤。我们的项目“肝窦的代谢分析”旨在将脂肪变性和手术引起的肝脏灌注变化与肝细胞代谢控制的变化以及肝窦水平上的线粒体功能联系起来。 大鼠模型。我们将提供关于碳水化合物和脂质代谢的区域分布和动力学的未知定量数据，这些数据受脂质超载和肝脏手术引起的灌注变化的调节。此外，我们将未知的带状线粒体活性定义为碳水化合物和脂质代谢的函数，并将流量限制引起的线粒体功能障碍识别为术后肝衰竭的潜在病理机制。最后，我们将提供定量数据，用于输入组织和细胞规模的碳水化合物和脂质代谢模拟模型。因此，该项目为研究单位在组织和细胞水平上的联合项目中的计算建模提供数据，并支持阐明肝脏手术背景下代谢分区灌注控制的生物机制。研究单元项目的相互迭代交互将支持模型验证和实验文本细化，以改进模型预测和实验策略。