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: 7935261
• 负责人: SANGEETA N. BHATIA
• 金额: $ 112.63万
• 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/7935261
• 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; Pharmaceutical Preparations; Plasmodium; Play; Polymerase; Predisposition; Primary carcinoma of the liver cells; Reporting; Resistance; Role; Structure; System; Technology; Therapeutic Intervention; Tissue Engineering; Tissues; Toxic effect; Transplantation; Virus; Virus Diseases; drug testing; effective therapy; global health; in vivo; inhibitor/antagonist; interdisciplinary approach; novel; outcome forecast; pathogen; public health relevance; reconstitution; tissue culture; vaccine development; vaccine efficacy; virology; virus virus interaction

DESCRIPTION (provided by applicant): The human liver serves as the reservoir for several important human pathogens, including hepatitis B (HBV) and C viruses (HCV) 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. PUBLIC HEALTH RELEVANCE: Hepatitis B and C viruses are leading causes of human liver disease including cancer. This proposal aims to create and utilize novel primary human hepatocyte tissue culture systems and complex 3D liver organoids to study HCV and HBV mono- and co-infections. The resulting findings should aid development of more effective treatments aimed at eradicating these deadly viral diseases.

描述（由申请人提供）：人类肝脏充当几种重要人类病原体的储层，包括乙型肝炎（HBV）和C病毒（HCV）和疟原虫物种，所有这些都代表了严重的全球健康问题。仅HBV和HCV就长期感染了全球估计有5亿人，年死亡人数超过150万。慢性HBV和HCV感染可能会带来严重的健康后果，包括肝炎，肝硬化，肝衰竭和肝细胞癌。与HBV和HCV共同感染很常见，并导致预后明显较差。 HBV的预防性疫苗存在，但靶向病毒的治疗疗法不可用。此外，据报道，HBV耐药性的增加增加了一线抗病毒药物。尚未开发用于HCV的疫苗，尽管HCV特异性蛋白酶和聚合酶抑制剂在早期临床发育中表现出希望，但耐药的迅速出现表明，需要其他抗病毒药物的靶标和组合才能有效控制。体外和体内系统的稀缺性忠实地模仿肝脏生物学和对人肝病病原体的敏感性严重阻碍了药物和疫苗的发育。在这里，我们建议采用跨学科的方法，并将组织工程与分子病毒学和人源化小鼠技术相结合，以创建平台，以促进基本病毒宿主和病毒 - 病毒相互作用的研究，促进对肝病进展机制的理解，并为预测系统提供预测性系统来测试药物和疫苗的效率和毒性和毒素。具体而言，我们旨在表征微图案原代人肝细胞培养物（MPCC）中HBV和HCV生物学以及模型相关的肝病 - Sangeeta Bhatia博士实验室最近开发的一项突破性技术。我们将扩展这种方法来开发三维肝癌，并研究用这些结构移植的小鼠中的HBV和HCV感染。由于慢性炎症在肝脏疾病进展中起着重要作用，因此我们旨在将免疫系统的组成部分纳入静态和动态组织培养系统中，并最终使用与人类造血系统接受者重建的小鼠HBV/HCV/HCV-疗法 - 疗程肝动物。通过这些平台的开发和使用，我们希望能阐明HBV和HCV病毒学和发病机理，并发现用于治疗干预的新途径。 公共卫生相关性：丙型肝炎和C病毒是包括癌症在内的人类肝病的主要原因。该建议旨在创建和利用新型的原发性人肝细胞组织培养系统和复杂的3D肝脏类器官来研究HCV和HBV单和共感染。结果的发现应有助于开发旨在消除这些致命病毒疾病的更有效的治疗方法。