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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK080942-02
Application #
7595903
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-04-01
Project End
2010-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2009
Total Cost
$89,999
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Badylak, Stephen F; Taylor, Doris; Uygun, Korkut (2011) Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu Rev Biomed Eng 13:27-53
Uygun, K; Tolboom, H; Izamis, M L et al. (2010) Diluted blood reperfusion as a model for transplantation of ischemic rat livers: alanine aminotransferase is a direct indicator of viability. Transplant Proc 42:2463-7
Uygun, Korkut; Uygun, Basak; Matthew, Howard W T et al. (2010) Optimization-based metabolic control analysis. Biotechnol Prog 26:1567-79
Uygun, Basak E; Soto-Gutierrez, Alejandro; Yagi, Hiroshi et al. (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16:814-20
Roach, Kenneth L; King, Kevin R; Uygun, Korkut et al. (2009) High-throughput single cell arrays as a novel tool in biopreservation. Cryobiology 58:315-21
Tolboom, Herman; Pouw, Roos E; Izamis, Maria-Louisa et al. (2009) Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion. Transplantation 87:170-7
Tolboom, H; Milwid, J M; Izamis, M L et al. (2008) Sequential cold storage and normothermic perfusion of the ischemic rat liver. Transplant Proc 40:1306-9