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.

人类肝脏是多种重要人类病原体的储存库，包括乙型肝炎 C 病毒和疟原虫种类，所有这些都代表着严重的全球健康问题。 据估计，仅 HCV 就慢性感染了全世界 5 亿人，每年死亡人数超过 150 万人慢性乙型肝炎和丙型肝炎病毒感染可造成严重的健康后果，包括肝炎、 乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）共同感染导致肝硬化、肝功能衰竭和肝细胞癌。 存在明显更差的乙型肝炎预防疫苗，但治疗方法针对的是乙型肝炎病毒。 此外，据报道，一线抗病毒药物 A 的耐药性增加。 HCV 疫苗尚未开发出来，虽然 HCV 特异性蛋白酶和聚合酶抑制剂正在开发中 在早期临床开发中显示出希望，耐药性的迅速出现表明额外的目标 有效控制需要抗病毒药物的组合。 忠实地模仿肝脏生物学和对人类嗜肝病原体的易感性严重阻碍了 在这里，我们建议采取跨学科的方法并将组织结合起来。 利用分子病毒学和人源化小鼠技术进行工程设计，创建平台，促进 研究基本病毒与宿主以及病毒与病毒相互作用，促进对肝脏机制的了解 疾病进展，并提供预测系统来测试药物和疫苗的功效和毒性。 我们的目标是表征 HBV 和 HCV 生物学特征，并建立微图案原发性肝病模型 人类肝细胞培养物 (MPCC) ¿博士最近开发的一项突破性技术 桑吉塔·巴蒂亚¿我们将扩展这种方法来开发三维肝脏类器官， 并研究移植这些结构的小鼠的慢性炎症后的 HBV 和 HCV 感染情况。 在肝脏疾病进展中发挥重要作用，我们的目标是整合免疫系统的组成部分 在静态和动态组织培养系统中，并最终使用与人类重组的小鼠 通过开发和使用，造血系统受者可获得 HBV/HCV 许可的肝脏类器官。 通过这些平台，我们希望阐明 HBV 和 HCV 病毒学和发病机制，并发现新的机制 治疗干预的途径。