Delineating cell type, mechanism, consequences and targeting of TGF-β2 expression in biliary liver disease

胆汁性肝病中 TGF-β2 表达的细胞类型、机制、后果和靶向的描述

• 批准号: 459725563
• 负责人: Dr. Anne Dropmann, Ph.D.
• 金额: --
• 依托单位: II. Medizinische Klinik: Gastroenterologie, Hepatologie, Infektiologie
• 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/459725563?language=en
• 关键词: Delineating; cell; type; mechanism; consequences

Chronic liver diseases (CLD) are a major health concern since fibrotic deteriorations progress to cirrhosis and liver cancer, the second deadliest cancer type worldwide. Primary sclerosing cholangitis (PSC) belongs to rare chronic autoimmune liver diseases that lead to the destruction of the biliary system. Starting with liver damage from persistent cholestasis, chronic portal inflammation and fibrosis in proximity of intrahepatic and extrahepatic bile ducts lead to cirrhotic rearrangements that compromise liver function. These PSC patients exhibit a 10–15% lifetime risk to develop cholangiocarcinoma (CCA).As liver transplantation is the only curative treatment opportunity so far, new therapeutic options are needed for the management of PSC. We recently identified TGF-β2 as specific biomarker and new potential treatment target for PSC, and possibly also for CCA. In this project, we aim to delineate in much detail the impact of TGF-β2 on CLD progression in PSC to justify a future clinical trial in patients. Specifically, we will analyse TGF-β2 expression regulation and TGF-β2 mediated signal transduction in the liver in a spatial and cell type specific manner during cholestatic disease progression in the ABCB4KO mouse model and in human PSC specimen. Furthermore, we will perform acute and chronic treatment of wildtype and ABCB4KO mice with TGF-β2 injection, at early intermediate and late disease stages, and depict the impact of TGF-β2 on parenchymal and non-parenchymal cell types, on liver (patho)morphology, and in particular fibrogenesis and inflammation. Thus, we will get insights on the role of TGF-β2 in the pathogenesis of biliary liver damage and disease progression in highest resolution, including a discrimination between TGF-β2 and TGF-β1 effects. Finally, we will target TGF-β2 expression using an established antisense oligonucleotide in CCA patient-derived organoids, as a preliminary test for a potential beneficial impact on tumor progression by estimating tumor growth, proliferative activity, stroma composition and chemoresistance. The project results will provide insight in the basics of TGF-β2 biology, specifically in liver cells and in the context of cholestatic liver disease and PSC. Data will also facilitate decision making in setting up a TGF-β2 directed clinical trial in PSC patients. Finally, we hope to see evidence that targeting TGF-β2 is a promising new treatment approach for patients with CCA.

慢性肝病（CLD）是一个主要的健康问题，因为纤维化恶化进展为肝硬化和肝癌，世界上第二大致命的癌症类型。原发性硬化性胆管炎（PSC）是一种罕见的慢性自身免疫性肝病，可导致胆道系统的破坏。从持续胆汁淤积引起的肝脏损害开始，肝内和肝外胆管附近的慢性门静脉炎症和纤维化导致肝硬化重排，损害肝功能。这些PSC患者一生中发生胆管癌（CCA）的风险为10-15%。由于肝移植是迄今为止唯一的治愈性治疗机会，因此需要新的治疗方案来治疗PSC。我们最近发现TGF-β2是PSC的特异性生物标志物和新的潜在治疗靶点，也可能是CCA的治疗靶点。在这个项目中，我们的目标是更详细地描述TGF-β2对PSC中CLD进展的影响，以证明未来在患者中的临床试验是合理的。具体而言，我们将在ABCB4KO小鼠模型和人PSC标本中，以空间和细胞类型特异性的方式分析肝脏中TGF-β2表达调控和TGF-β2介导的信号转导在胆汁淤滞性疾病进展过程中的作用。此外，我们将在疾病早期、中期和晚期对野生型和ABCB4KO小鼠进行急性和慢性TGF-β2注射治疗，并描述TGF-β2对实质细胞和非实质细胞类型、肝脏（病理）形态，特别是纤维化和炎症的影响。因此，我们将以最高分辨率深入了解TGF-β2在胆道性肝损伤的发病机制和疾病进展中的作用，包括区分TGF-β2和TGF-β1的作用。最后，我们将利用一种已建立的反义寡核苷酸在CCA患者来源的类器官中靶向TGF-β2的表达，通过评估肿瘤生长、增殖活性、基质组成和化疗耐药性，作为对肿瘤进展潜在有益影响的初步测试。该项目的结果将为TGF-β2生物学的基础知识提供见解，特别是在肝细胞和胆汁淤积性肝病和PSC的背景下。数据也将有助于在PSC患者中建立TGF-β2导向临床试验的决策。最后，我们希望有证据表明靶向TGF-β2是治疗CCA患者的一种有前景的新方法。