MICA: Molecular drivers of fibrosis at the hepatic epithelial-mesenchymal barrier

MICA：肝上皮间质屏障纤维化的分子驱动因素

• 批准号: MR/R023026/1
• 负责人: Derek Mann
• 金额: $ 195.44万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR023026%2F1
• 关键词: MICA; Molecular; drivers; fibrosis; hepatic

Chronic liver disease (CLD) is a major cause of death, being responsible for over one million early fatalities in 2010, equating to 2% of all deaths worldwide. These statistics are reliably expected to rise over the coming decade, in major part as a consequence of non-alcoholic fatty liver disease (NAFLD), a dangerous pathology of the liver that affects 20% of the global population, which is closely associated with diabetes and obesity. Up to 30% of patients with NAFLD can progress to end stage disease known as cirrhosis. Therefore, cirrhosis may potentially be impacting on 5% of the world population including millions of children and young adults. In addition to this shocking statistic, 350 million people are infected with the hepatitis B virus leading to 40,000 deaths per annum in Europe alone, 150 million are infected with hepatitis C causing 500,000 liver-related deaths each year. Furthermore, CLD carries a high risk of liver cancer, now the second most common cause of cancer-related deaths worldwide, preceded only by lung cancer. While arguably NAFLD may respond to lifestyle interventions; lack of robust clinical guidelines and challenges associated with patient compliance for dietary/exercise changes necessitate a multifaceted approach for care of CLD. Paramount to this approach is the urgent and unmet need for medicines that slow, halt or even reverse the disease pathway to cirrhosis and associated risk of cancer. This MICA research programme will benefit from collaboration of world-leading liver disease investigators of the Newcastle Fibrosis Research Group (NFRG) and the scientific power and resources of the global pharmaceutical company GSK. The aim of the proposed research is to understand how damage to liver cells leads to cirrhosis and to translate this research into the design of new medicines and diagnostics that bring benefit to CLD patients. Study of the biology of CLD reveals commonalities that characterize the disease irrespective of the cause of liver injury. These characteristics include repetitive damage to hepatocytes which are the main cell type in the liver, unresolved inflammation and aberrant liver tissue remodeling involving the progressive laying-down of non-functional scar tissue that gradually replaces functional liver cell mass. Scar-formation is known as fibrosis and can occur in any organ where there is repetitive cellular damage. Fibrotic scars in the liver are produced by myofibroblasts generated by 'activation' of resident specialized hepatic stellate cells in response to liver damage. Modulating the activities of the myofibroblast has the potential to halt or even reverse fibrosis. Based on preliminary data from NFRG and GSK we propose that repetitive damage to hepatocytes changes their molecular characteristics such that they repeatedly signal a need to generate scar tissue to nearby myofibroblasts. We aim to discover the nature of the molecular changes occurring in damaged hepatocytes and identify the signals they communicate to the myofibroblast. As NAFLD is such a major global concern an important focus will be placed on determining how the uptake of excess fats into hepatocytes alters their biology to stimulate fibrosis.Much of the research will make use of human liver tissue made possible by recent exciting technological advances in the NFRG laboratories. It is now possible to 'model' NAFLD in thin slices of liver tissue. Using this advance alongside modern molecular biology approaches we will discover so-called 'epigenetic' drivers that operate within fat-laden hepatocytes to stimulate fibrosis. These drivers can be exploited for the design of new blood tests that tell us which NAFLD patients are at risk from cirrhosis as well as guiding us on where to target the development of new therapies. By partnering with GSK there is tremendous opportunity for discoveries emerging from the research to be translated to healthcare products for patient benefit.

慢性肝病（CLD）是死亡的主要原因，在2010年造成超过100万例早期死亡，相当于全球所有死亡的2%。预计这些统计数据在未来十年内将可靠地上升，主要是由于非酒精性脂肪肝病（NAFLD），这是一种影响全球20%人口的危险肝脏病理学，与糖尿病和肥胖密切相关。高达30%的NAFLD患者可以进展为称为肝硬化的终末期疾病。因此，肝硬化可能影响世界人口的5%，包括数百万儿童和年轻人。除了这一令人震惊的统计数据外，仅在欧洲，每年就有3.5亿人感染B型肝炎病毒，导致40，000人死亡，每年有1.5亿人感染丙型肝炎，导致500，000例肝脏相关死亡。此外，CLD具有肝癌的高风险，肝癌现在是全球癌症相关死亡的第二大常见原因，仅次于肺癌。虽然可以说NAFLD可能对生活方式干预有反应;但缺乏强有力的临床指南以及与患者对饮食/运动改变的依从性相关的挑战，需要多方面的方法来治疗CLD。对这种方法至关重要的是对减缓、停止甚至逆转肝硬化和相关癌症风险的疾病途径的药物的迫切和未满足的需求。这项云母研究计划将受益于纽卡斯尔纤维化研究小组（NFRG）世界领先的肝病研究人员的合作以及全球制药公司GSK的科学力量和资源。这项研究的目的是了解肝细胞损伤如何导致肝硬化，并将这项研究转化为新药物和诊断的设计，为CLD患者带来益处。CLD的生物学研究揭示了无论肝损伤的原因如何，该疾病的共同特征。这些特征包括对肝细胞的重复性损伤，肝细胞是肝脏中的主要细胞类型，未解决的炎症和异常的肝组织重塑，涉及逐渐取代功能性肝细胞团的非功能性瘢痕组织的进行性沉积。瘢痕形成被称为纤维化，可以发生在任何有重复性细胞损伤的器官中。肝脏中的纤维化瘢痕由肌成纤维细胞产生，所述肌成纤维细胞由响应于肝损伤的常驻特化肝星状细胞的“激活”产生。调节肌成纤维细胞的活性有可能阻止甚至逆转纤维化。基于NFRG和GSK的初步数据，我们提出肝细胞的重复损伤改变了它们的分子特征，使得它们反复向附近的肌成纤维细胞发出需要产生瘢痕组织的信号。我们的目标是发现受损肝细胞中发生的分子变化的性质，并确定它们与肌成纤维细胞沟通的信号。由于NAFLD是一个全球性的重大问题，因此将重点关注如何确定肝细胞摄取过量脂肪改变其生物学以刺激纤维化。许多研究将利用NFRG实验室最近令人兴奋的技术进步所带来的人类肝脏组织。现在可以在肝脏组织的薄片中“模拟”NAFLD。利用这一进展以及现代分子生物学方法，我们将发现所谓的“表观遗传”驱动程序，这些驱动程序在富含脂肪的肝细胞内运作，以刺激纤维化。这些驱动因素可以用于设计新的血液检测，告诉我们哪些NAFLD患者有肝硬化的风险，并指导我们开发新疗法的目标。通过与GSK的合作，将研究中的发现转化为医疗保健产品以造福患者，这是一个巨大的机会。

项目成果

Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach.

• DOI: 10.1038/s41575-023-00796-x
• 发表时间: 2023-10
• 期刊: Nature reviews. Gastroenterology & hepatology

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection.

• DOI: 10.15252/embj.2021108970
• 发表时间: 2022-12-01
• 期刊: The EMBO journal

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis.

• DOI: 10.4049/jimmunol.2001022
• 发表时间: 2021-02-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Bianchi A;Marchetti L;Hall Z;Lemos H;Vacca M;Paish H;Green K;Elliott B;Tiniakos D;Passos JF;Jurk D;Mann DA;Wilson CL
• 通讯作者: Wilson CL

Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression.

• DOI: 10.1016/j.molmet.2021.101210
• 发表时间: 2021-06
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Azzu V;Vacca M;Kamzolas I;Hall Z;Leslie J;Carobbio S;Virtue S;Davies SE;Lukasik A;Dale M;Bohlooly-Y M;Acharjee A;Lindén D;Bidault G;Petsalaki E;Griffin JL;Oakley F;Allison MED;Vidal-Puig A
• 通讯作者: Vidal-Puig A

Quantification of intra-articular fibrosis in patients with stiff knee arthroplasties using metal-reduction MRI.

• DOI: 10.1302/0301-620x.102b10.bjj-2020-0841.r1
• 发表时间: 2020-10
• 期刊: The bone & joint journal
• 作者: Attard V;Li CY;Self A;Mann DA;Borthwick LA;O'Connor P;Deehan DJ;Kalson NS
• 通讯作者: Kalson NS