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.

Public Health 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Serrano, Jose
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Massachusetts General Hospital
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Bruinsma, Bote G; Berendsen, Tim A; Izamis, Maria-Louisa et al. (2015) Supercooling preservation and transplantation of the rat liver. Nat Protoc 10:484-94
Izamis, Maria-Louisa; Perk, Sinem; Calhoun, Candice et al. (2015) Machine perfusion enhances hepatocyte isolation yields from ischemic livers. Cryobiology 71:244-55
Bruinsma, Bote G; Wu, Wilson; Ozer, Sinan et al. (2015) Warm ischemic injury is reflected in the release of injury markers during cold preservation of the human liver. PLoS One 10:e0123421
Bruinsma, B G; Yeh, H; Ozer, S et al. (2014) Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. Am J Transplant 14:1400-9
Berendsen, Tim A; Bruinsma, Bote G; Puts, Catheleyne F et al. (2014) Supercooling enables long-term transplantation survival following 4 days of liver preservation. Nat Med 20:790-3
Bruinsma, Bote G; Yarmush, Martin L; Uygun, Korkut (2014) Organomatics and organometrics: Novel platforms for long-term whole-organ culture. Technology (Singap World Sci) 2:13
Usta, O Berk; Kim, Yeonhee; Ozer, Sinan et al. (2013) Supercooling as a viable non-freezing cell preservation method of rat hepatocytes. PLoS One 8:e69334
Izamis, Maria-Louisa; Tolboom, Herman; Uygun, Basak et al. (2013) Resuscitation of ischemic donor livers with normothermic machine perfusion: a metabolic flux analysis of treatment in rats. PLoS One 8:e69758
Liu, Qiang; Izamis, Maria-Louisa; Xu, Hongzhi et al. (2013) Strategies to rescue steatotic livers before transplantation in clinical and experimental studies. World J Gastroenterol 19:4638-50
Bruinsma, Bote G; Berendsen, Tim A; Izamis, Maria-Louisa et al. (2013) Determination and extension of the limits to static cold storage using subnormothermic machine perfusion. Int J Artif Organs 36:775-80

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