Computer-aided Development of a Liver Organ Culture System

肝器官培养系统的计算机辅助开发

• 批准号: 7450387
• 负责人: Korkut Uygun
• 金额: $ 9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450387
• 关键词: Advisory Committees; Applications Grants; Bile fluid; Biochemical Pathway; Biomedical Engineering; Calculi; Cardiac Death; Cessation of life; Chemical Engineering; Chronic; Cirrhosis; Complex; Computer Assisted; Computer Simulation; Condition; Cryopreservation; Data; Deposition; Development; Development Plans; Disease; Employment; Engineering; Environment; Fatty Liver; Fibrosis; General Hospitals; Goals; Gold; Hand; Hepatocyte; Hour; Ischemia; Lipids; Liver; Liver Failure; Liver diseases; Mammalian Cell; Massachusetts; Medicine; Metabolic; Methodology; Methods; Mitochondria; Modeling; Natural regeneration; Numbers; Operative Surgical Procedures; Organ; Organ Culture Techniques; Organ Donor; Organ Preservation; Oxygen; Patients; Perfusion; Personal Satisfaction; Probability; Production; Public Health; Purpose; Rattus; Reperfusion Injury; Research; Research Personnel; Resuscitation; Simulate; Solutions; Standards of Weights and Measures; Study Section; System; Systems Biology; Technology; Testing; Time; Training; Transplantation; Urea; Waiting Lists; Work; base; body system; career; desire; improved; innovation; interest; liver function; liver metabolism; liver preservation; liver transplantation; mathematical model; medical schools; microorganism; novel; nutrition; prevent; professor; programs; repaired; success; tool; uptake

DESCRIPTION (provided by applicant): This is a career grant application for Dr. Uygun; a chemical engineer by training who specializes in mathematical modeling and optimization of complex systems. Dr. Uygun has recently developed novel methods of modeling hepatocytes, and his interests have shifted to application of such tools to biomedical engineering. To establish himself as an independent researcher in the field of biomedical systems engineering, Dr. Uygun submits this five-year career development plan under the sponsorship of Dr. Martin Yarmush, the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School and the director of the Center for Engineering in Medicine at the Massachusetts General Hospital, which includes i) intensive hand-on training in biomedical engineering and isolated liver perfusion, ii)academic courses and seminars, and iii) guidance of a select advisory committee. Project Summary: The long-term goals of this research are to develop liver metabolic engineering methodologies for curing or treating relevant diseases including steatosis and fibrosis, and reducing deaths due to liver failure in general. The objectives of the proposed study are to develop paired in silico and ex vivo perfused liver models, and utilize them for metabolic engineering of marginal livers to increase the donor pool. The central hypothesis to be tested here is that the liver can be maintained functionally ex vivo for extended periods by optimal metabolic modulation, and this organ culture system can be employed for resuscitating ischemic livers and defatting steatotic livers for transplantation. The rationale is that the development of an in silico liver model that correlates metabolic activity and viability will enable simulating a large number of metabolic modulation strategies efficiently, identifying a limited number of candidate solutions for defatting of repleting energy levels, hence rendering metabolic optimization of perfused livers practical within the project period. The work described here is expected to i) establish normothermic extracorporeal perfusion as a feasible means of functional liver storage, ii) generate an in silico model of the isolated perfused rat liver that correlates metabolic functioning, liver damage and transplant success, and iii) establish novel methods to enable transplantation of marginal livers, thereby reducing liver failure related deaths. The results of this work will also have a positive impact on organ scale research of the liver, such as steatosis, fibrosis and regeneration, by providing a stable and well-characterized system as their basis. Relevance to public health: Chronic liver disease and cirrhosis causes about 27,000 deaths annually in the US, 2,500 of which perish on the waiting list for liver transplant. A major reason of liver related deaths is the limited donor pool. This project aims to improve public health by utilizing currently discarded donor livers by reconditioning them to be transplantable with success.

描述（由申请人提供）： 这是Uygun博士的职业资助申请;他是一名化学工程师，专门从事复杂系统的数学建模和优化。Uygun博士最近开发了肝细胞建模的新方法，他的兴趣已经转移到将这些工具应用于生物医学工程。为了使自己成为生物医学系统工程领域的独立研究员，Uygun博士在哈佛医学院外科和生物工程的Helen Andrus Benedict教授和马萨诸塞州总医院医学工程中心主任Martin Yarmush博士的赞助下提交了这份五年职业发展计划，其中包括i）生物医学工程和隔离肝脏灌注方面的强化实践培训，ii）学术课程和研讨会，以及iii）精选咨询委员会的指导。项目概要：这项研究的长期目标是开发肝脏代谢工程方法，用于治愈或治疗相关疾病，包括脂肪变性和纤维化，并减少因肝功能衰竭而导致的死亡。拟议研究的目标是开发成对的计算机模拟和离体灌注肝脏模型，并利用它们进行边缘肝脏的代谢工程，以增加供体库。这里要测试的中心假设是，肝脏可以通过最佳的代谢调节在体外维持功能性延长时间，并且该器官培养系统可以用于复苏缺血肝脏和脱脂脂肪变性肝脏用于移植。其基本原理是，将代谢活性和活力相关联的计算机模拟肝脏模型的开发将能够有效地模拟大量的代谢调节策略，识别有限数量的候选解决方案，用于消除补充能量水平的脂肪，从而在项目期间实现灌注肝脏的代谢优化。本文所述的工作预计i）建立常温体外灌注作为功能性肝脏储存的可行方法，ii）生成与代谢功能、肝损伤和移植成功相关的分离灌注大鼠肝脏的计算机模拟模型，以及iii）建立能够移植边缘肝的新方法，从而减少肝衰竭相关死亡。这项工作的结果也将对肝脏的器官规模研究产生积极的影响，如脂肪变性，纤维化和再生，通过提供一个稳定和良好表征的系统作为其基础。与公共卫生的相关性：慢性肝病和肝硬化每年在美国造成约27，000人死亡，其中2，500人在等待肝脏移植的名单上死亡。肝脏相关死亡的一个主要原因是有限的供体库。该项目旨在通过利用目前被丢弃的捐赠肝脏来改善公共卫生，通过修复它们以使其能够成功移植。