Importance of the non-physiological activation of the mineralocorticoid receptor for progression and development of complication in cirrhosis

盐皮质激素受体的非生理激活对于肝硬化并发症进展和发展的重要性

• 批准号: 433796843
• 负责人: Privatdozentin Dr. Barbara Schreier
• 金额: --
• 依托单位: Julius-Bernstein-Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433796843?language=en
• 关键词: Importance; non; physiological; activation; mineralocorticoid

Our previous results showed less progression of cirrhosis due to administration of the mineralocorticoid receptor (MR) antagonist Eplerenon during development of cirrhosis defined by less development of ascites, lower portal pressure, less shunts and less fibrotic tissue. An unphysiological activation of the MR under hypoxia and inhibition by Eplereonon was revealed as underlying mechanism.The aim of the proposal is the mechanistic characterisation of the MR in development and progression of cirrhosis. We want to clarify the role of the MR and the knowledge about the pathophysiology of the progress from fibrosis to cirrhosis and of decompensation for novel therapeutic strategies and prevention of disease progression. The following sub-projects are planned:A: Molecular systematics and mechanism of the altered MR expression and activation in hepatocytes.In primary hepatocytes the transcription, translocation and degradation of the MR in absence or presence of relevant stress conditions are planned to explain the lower concentration of the MR in cirrhosis. Cell lines (siRNA-transfection) are used to investigate molecular pathways in detail. B: Cellular changes and influence of cell-cell interaction by the unphysiological activation of the MR and its inhibition.The importance of the MR by measurement of specific MR-related genes for development of cirrhosis in presence or absence of Eplerenon will be investigated in different stages of fibrosis and cirrhosis. Upstream and downstream relevance of these findings will be further investigated. Cell-cell interaction from hepatocytes, stellate cells and sinusoidal endothelial cells in different stages of fibrosis and cirrhosis are planned to clarify the functional properties of the different cells and the importance of cell-cell communication using coculture with or without cell-cell contact. C: Importance of the unphysiological activation in cirrhosis for liver perfusion, vascular dysfunction and vascular endothelial phenotype.The importance of the MR for portal-venous and hepatic arterial dysfunction in cirrhosis will be investigated by using liver perfusion models. Functional properties of the portal vein and the hepatic artery will be determined by Mulvany-Myography and isometric contraction. Endothelial cells from portal veins and hepatic arteries will be cultured and receptors, growth factors and secondary mediators investigated.

我们以前的研究结果表明，由于在肝硬化发展过程中给予盐皮质激素受体（MR）拮抗剂依普利农，肝硬化进展较少，定义为腹水发展较少，门静脉压力较低，分流较少和纤维化组织较少。缺氧和Epreonon抑制下的MR的非生理性激活被揭示为潜在的mechanism.The建议的目的是MR的发展和进展的肝硬化的机制表征。我们希望阐明MR的作用以及从纤维化到肝硬化进展的病理生理学知识，以及新的治疗策略和预防疾病进展的失代偿。计划开展以下子项目：A：肝细胞中MR表达和激活改变的分子系统学和机制。计划在原代肝细胞中，在缺乏或存在相关应激条件下，MR的转录、易位和降解，以解释肝硬化中MR浓度较低的原因。细胞系（siRNA转染）用于详细研究分子途径。B：通过MR的非生理性激活及其抑制的细胞变化和细胞-细胞相互作用的影响。在纤维化和肝硬化的不同阶段，将研究在存在或不存在依普利农的情况下，通过测量特定MR相关基因对肝硬化发展的MR的重要性。将进一步调查这些发现的上游和下游相关性。计划在纤维化和肝硬化的不同阶段中从肝细胞、星状细胞和窦状内皮细胞的细胞-细胞相互作用来阐明不同细胞的功能特性和使用有或没有细胞-细胞接触的共培养的细胞-细胞通信的重要性。丙：肝硬化非生理性激活对肝脏灌注、血管功能障碍和血管内皮表型的重要性。MR对肝硬化门静脉和肝动脉功能障碍的重要性将通过使用肝脏灌注模型来研究。门静脉和肝动脉的功能特性将通过Mulvany-Myography和等长收缩来确定。将培养门静脉和肝动脉的内皮细胞，并研究受体、生长因子和次级介质。