Modeling human hepatotropic infections in complex tissue organoids

在复杂组织类器官中模拟人类嗜肝感染

• 批准号: 8322073
• 负责人: SANGEETA N. BHATIA
• 金额: $ 111.06万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322073
• 关键词: Antiviral Agents; Biology; Cessation of life; Chronic; Cirrhosis; Clinical; Complex; Development; Disease Progression; HCV Vaccine; Health; Hematopoietic System; Hepatitis; Hepatitis B; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune system; In Vitro; Infection; Inflammation; Laboratories; Light; Liver; Liver Failure; Liver diseases; Malignant Neoplasms; Methodology; Modeling; Molecular Virology; Mono-S; Mus; Organoids; Pathogenesis; Peptide Hydrolases; Plasmodium; Play; Polymerase; Predisposition; Primary carcinoma of the liver cells; Reporting; Resistance; Role; Structure; System; Technology; Testing; Therapeutic Intervention; Tissue Engineering; Tissues; Toxic effect; Transplantation; Virus; Virus Diseases; drug development; drug efficacy; effective therapy; global health; in vivo; inhibitor/antagonist; interdisciplinary approach; novel; outcome forecast; pathogen; reconstitution; tissue culture; vaccine development; vaccine efficacy; virology; virus virus interaction

The human liver serves as the reservoir for several important human pathogens, including hepatitis B and C viruses and Plasmodium species, all of which represent serious global health concerns. HBV and HCV alone chronically infect an estimated 500 million people worldwide, with annual deaths totaling more than 1.5 million. Chronic HBV and HCV infections can have severe health consequences, including hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Co-infection with HBV and HCV is common, and leads to a significantly worse prognosis. A preventative vaccine for HBV exists, but curative treatments targeting the virus are not available. Furthermore, increasing HBV resistance has been reported to first-line antiviral drugs. A vaccine for HCV has not yet been developed, and, while HCV-specific protease and polymerase inhibitors are showing promise in early clinical development, rapid emergence of resistance indicates that additional targets and combinations of antivirals will be needed for effective control. The scarcity of in vitro and in vivo systems that faithfully mimic liver biology and susceptibility to human hepatotropic pathogens has severely hampered drug and vaccine development. Here, we propose to take an interdisciplinary approach and combine tissue engineering with molecular virology and humanized mouse technology to create platforms that will facilitate studies of basic virus-host and virus-virus interactions, promote understanding of the mechanisms of liver disease progression, and provide predictive systems to test drug and vaccine efficacy and toxicity. Specifically, we aim to characterize HBV and HCV biology and model associated liver disease in micropatterned primary human hepatocyte cultures (MPCCs) ¿ a breakthrough technology that was recently developed in Dr. Sangeeta Bhatia¿s laboratory. We will extend this methodology to develop three-dimensional liver organoids, and investigate HBV and HCV infection in mice transplanted with these structures. Since chronic inflammation plays a significant role in liver disease progression, we aim to incorporate components of the immune system in static and dynamic tissue culture systems and ultimately to use mice reconstituted with a human hematopoietic system recipients for HBV/HCV-permissive liver organoids. Through the development and use of these platforms, we hope to shed light on HBV and HCV virology and pathogenesis, and to uncover novel avenues for therapeutic intervention.

人的肝脏是几种重要的人类病原体的储存库，包括乙肝 以及C病毒和疟原虫物种，所有这些都代表着严重的全球健康问题。乙肝病毒和 仅丙型肝炎病毒一项就慢性感染了全世界约5亿人，每年死亡总数超过 150万。慢性乙肝病毒和丙型肝炎病毒感染可能会造成严重的健康后果，包括肝炎， 肝硬变、肝功能衰竭和肝细胞癌。与乙肝病毒和丙型肝炎病毒混合感染很常见，并导致 预后明显更差。有一种预防乙肝的疫苗存在，但针对 病毒不可用。此外，据报道，一线抗病毒药物增加了对乙肝病毒的耐药性。一个 丙型肝炎病毒的疫苗还没有开发出来，虽然丙型肝炎病毒特异性的蛋白酶和聚合酶抑制剂是 在早期临床开发中显示出希望，耐药性的快速出现表明有更多的靶点 有效的控制将需要抗病毒药物的联合使用。体外和体内系统的稀缺性 忠实地模仿肝脏生物学和对人类嗜肝病原体的敏感性严重阻碍了 药物和疫苗开发。在这里，我们建议采取跨学科的方法，将组织 利用分子病毒学和人性化鼠标技术进行工程设计，以创建将促进 研究基本的病毒-宿主和病毒-病毒相互作用，促进对肝脏机制的理解 疾病进展，并提供预测系统，以测试药物和疫苗的有效性和毒性。具体来说， 我们的目标是在微模式的原发病例中研究乙肝病毒和丙型肝炎的生物学特征和相关肝病的模型。 人类肝细胞培养(MPCCs)是一项突破性技术，最近由Dr。 S实验室。我们将把这一方法扩展到开发三维肝脏器官， 并研究移植了这些结构的小鼠的乙肝病毒和丙型肝炎病毒感染情况。由于慢性炎症 在肝脏疾病的发展中扮演着重要的角色，我们的目标是结合免疫系统的组件 在静态和动态组织培养系统中，并最终使用与人重组的小鼠 为乙肝病毒/丙型肝炎病毒允许的肝脏器官移植的造血系统受体。通过开发和使用 在这些平台中，我们希望阐明乙肝病毒和丙型肝炎病毒的病毒学和发病机制，并揭示新的 治疗干预的途径。