CAREER: Engineering a Liver Sinusoid Functional Unit

职业：设计肝脏正弦功能单元

• 批准号: 0747752
• 负责人: Hongseok Noh
• 金额: $ 45.89万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0747752&HistoricalAwards=false
• 关键词: CAREER; Engineering; Liver; Sinusoid; Functional

CBET-0747752NohA new approach to generate an authentic human liver model is proposed in this project. The liver lobule is composed of operational units termed the liver sinusoid, where most of the liver activities take place. Fundamental liver biology studies predominantly rely on cell culture models. While much progress has been made during the past two decades in prolonging hepatocyte viability and maintaining liver functions in vitro, there are still no authentic liver models that accurately represent the architecture and functions of human liver tissue, thereby limiting advances in liver biology studies and drug development.The goal of this research is to generate an innovative human liver model (bioreactor) that closely mimics the liver sinusoid functional unit. Microfabrication and microfluidics will be combined with cell culture technology to create such an authentic human liver model. The intellectual merits of this project are as follows. First, the relationship between cellular organization and cell-specific functions within the liver will be clarified. In particular, the roles and interactions of liver cells and the effects of the cellular microenvironment (specifically, culture media formulation, bile removal, and oxygen concentration) on maintaining liver-specific functions will be elucidated in the process of optimizing the authentic liver model. Computational and experimental studies will be combined for the optimization process. Second, this project will generate an authentic human liver model which is currently unavailable, and explore its applications. A novel bioreactor system with an authentic liver model will be developed for the study of cellular responses to stimuli. The availability of a liver model (bioreactor) that retains cellular phenotypes of a liver sinusoid functional unit will facilitate the analyses of many aspects of the molecular mechanisms that underlie hepatocyte, or other liver cell activities in a variety of areas such as toxicology, viral infection, cancer research, and drug/gene screening. To demonstrate the utility of the novel human liver model, a focused study that analyzes the effect of Hepatitus B virus (HBV) replication on specific hepatocyte signaling pathways is proposed. This study will unveil how HBV replication affects normal human hepatocyte physiology, which is currently unknown. This research will also have significant technical impacts on the pharmaceutical industry. An authentic human liver model can greatly help them identify targets, design and develop drugs, and test them to predict performance in human clinical trials. Development of human organ models will also be expanded to other internal organs such as the lung and the breast that have unique functional units. The broader impacts of this activity include an educational component to address the national lack of microfludics education in the current engineering and science curricula by developing a set of laboratory modules and kits. This Microfluidics Laboratory Modules and Kits will have significant educational impacts at different levels. Most of all, the novel lab modules and kits will provide engineering and science students (both undergraduate and graduate) opportunities to explore microfluidic phenomena and their biomedical applications through engaging lab classes. The lab modules and kits will be initially tested at Drexel University via two courses and then distributed to more diverse users. Faculty members at Cooper Union, Rowan University, University of Connecticut, Lincoln University*, and Cheyney University* (*historically minority institutions for higher education) are committed to test the lab modules and kits in their current courses and senior design projects. The lab modules and kits will also be used in outreach programs such as NSF-supported Research Experience for Teachers (RET) and NSF GK-12 to allow high school students and teachers to ?see and feel? miniature science, promoting their interests in science and engineering. The success of this project will lead to the commercialization of the Microfluidics Laboratory Kits for broader dissemination.

CBET-0747752 Noha本项目提出了一种生成真实人肝模型的新方法。肝小叶由称为肝窦的操作单元组成，大多数肝脏活动发生在肝窦中。 基础肝脏生物学研究主要依赖于细胞培养模型。虽然在过去的二十年中，在体外延长肝细胞活力和维持肝功能方面取得了很大进展，但仍然没有准确代表人类肝组织结构和功能的真实肝脏模型，从而限制了肝脏生物学研究和药物开发的进展。这项研究的目标是产生一个创新的人类肝脏模型（生物反应器），其紧密地模仿肝窦状隙功能单元。微加工和微流体技术将与细胞培养技术相结合，以创建这样一个真实的人类肝脏模型。这个项目的智力价值如下。首先，将阐明肝脏内细胞组织和细胞特异性功能之间的关系。特别是，肝细胞的作用和相互作用以及细胞微环境（特别是培养基配方，胆汁去除和氧浓度）对维持肝脏特异性功能的影响将在优化真实肝脏模型的过程中阐明。计算和实验研究相结合的优化过程。其次，本项目将生成一个目前无法获得的真实的人类肝脏模型，并探索其应用。一种新的生物反应器系统与真实的肝脏模型将被开发用于研究细胞对刺激的反应。保留肝窦功能单位的细胞表型的肝模型（生物反应器）的可用性将有助于分析肝细胞或其他肝细胞在各种领域（如毒理学、病毒感染、癌症研究和药物/基因筛选）中活动的分子机制的许多方面。为了证明新的人类肝脏模型的实用性，提出了一项重点研究，分析B肝炎病毒（HBV）复制对特定肝细胞信号传导途径的影响。这项研究将揭示HBV复制如何影响正常的人类肝细胞生理学，这是目前未知的。这项研究也将对制药行业产生重大的技术影响。一个真实的人类肝脏模型可以极大地帮助他们识别靶点，设计和开发药物，并测试它们以预测人体临床试验的性能。人体器官模型的开发也将扩展到其他具有独特功能单元的内脏器官，如肺和乳房。这项活动的更广泛影响包括一个教育部分，通过开发一套实验室模块和工具包，解决全国目前工程和科学课程中缺乏微流体教育的问题。该微流体实验室模块和套件将在不同层面上产生重大的教育影响。最重要的是，新的实验室模块和工具包将为工程和科学专业的学生（本科生和研究生）提供机会，通过引人入胜的实验室课程探索微流体现象及其生物医学应用。实验模块和工具包将在德雷克塞尔大学通过两门课程进行初步测试，然后分发给更多不同的用户。库珀联盟，罗文大学，康涅狄格大学，林肯大学 * 和切尼大学 *（* 历史上少数民族高等教育机构）的教师致力于在他们目前的课程和高级设计项目中测试实验室模块和工具包。实验模块和工具包也将用于外展计划，如NSF支持的教师研究经验（RET）和NSF GK-12，让高中学生和教师？看和感觉？微型科学，促进他们对科学和工程的兴趣。该项目的成功将导致微流体实验室套件的商业化，以更广泛地传播。