Molecular pathogenesis and signaling pathways: identification of therapeutic targets in primary sclerosing cholangitis (PSC)

分子发病机制和信号通路：原发性硬化性胆管炎 (PSC) 治疗靶点的鉴定

• 批准号: 417889840
• 负责人: Professor Dr. Christoph Schramm
• 金额: --
• 依托单位: I. Medizinische Klinik und Poliklinik
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/417889840?language=en
• 关键词: Molecular; pathogenesis; signaling; pathways; identification

Primary sclerosing cholangitis (PSC) is a serious inflammatory liver disease leading to liver cirrhosis, cancer, death or liver transplantation. Currently, there is no treatment available to alter the progressive nature of this disease. The pathogenesis of PSC is unknown, but a strong association with inflammatory bowel disease points to the contribution of immune dysregulation at mucosal surfaces. Within the Clinical Research Unit 306 (CRU "Primary Sclerosing Cholangitis") we are investigating the pathogenesis of PSC since the beginning of 2016. Acquisition of experimental data and human biosamples within the first two years of funding enable us now to decipher the molecular pathways leading to liver and intestinal pathology in PSC. We have revealed disease specific changes using immune-phenotyping of liver infiltrating and peripheral blood mononuclear cells by flow cytometry, but this method has the limitation that only few factors can be analyzed at a time in a biased approach. Thus, we aim here to deepen our knowledge using single cell RNA-sequencing, which allows us unbiased single cell analysis on a transcriptional level at a resolution, which has not been possible so far. Applying this novel technique on paired liver and blood derived mononuclear cells will allow us to characterize immune cells potentially involved in disease pathogenesis, and to identify disease specific cellular targets as well as mechanisms which increase homing to and retention of inflammatory cells in the liver. These analyses will be complemented by bulk liver transcriptome analyses from biopsies of patients at different stages of disease as well as from intestinal biopsies in order to identify drugable signaling pathways in immune and non-immune cells. Human samples from liver and intestine are ready to be analyzed and single cell sequencing will be performed within the first year of this application. Data integration and analysis will benefit from the experience of co-applicant SB, who is director of the Institute of Medical Systems Biology at the UKE.

原发性硬化性胆管炎（PSC）是一种严重的炎症性肝病，可导致肝硬化、肝癌、死亡或肝移植。目前，没有治疗方法可以改变这种疾病的进行性。PSC的发病机制尚不清楚，但与炎症性肠病的密切相关性表明粘膜表面的免疫失调。自2016年初以来，在临床研究单元306（CRU“原发性硬化性胆管炎”）中，我们正在研究PSC的发病机制。在资助的头两年内获得的实验数据和人类生物样本使我们现在能够破译导致PSC肝脏和肠道病理学的分子途径。我们已经通过流式细胞术使用肝脏浸润和外周血单核细胞的免疫表型分析揭示了疾病特异性变化，但这种方法具有局限性，即在有偏倚的方法中一次只能分析很少的因素。因此，我们的目标是使用单细胞RNA测序来加深我们的知识，这使得我们能够在转录水平上以一种分辨率进行无偏见的单细胞分析，这是迄今为止还不可能的。将这种新技术应用于配对的肝脏和血液来源的单核细胞将使我们能够表征可能参与疾病发病机制的免疫细胞，并鉴定疾病特异性细胞靶点以及增加肝脏中炎症细胞归巢和保留的机制。这些分析将通过来自不同疾病阶段患者活检以及肠活检的大量肝脏转录组分析进行补充，以鉴定免疫和非免疫细胞中的可药物化信号通路。来自肝脏和肠道的人类样本已准备好进行分析，单细胞测序将在本申请的第一年内进行。数据集成和分析将受益于共同申请人SB的经验，SB是UKE医学系统生物学研究所所长。