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Design and analysis of amino acid supplementation in hepatocyte culture using in vitro experiment and mathematical modeling
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Design and analysis of amino acid supplementation in hepatocyte culture using in vitro experiment and mathematical modeling
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ETD_2412
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000052170
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eng
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theses
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Topic
Chemical and Biochemical Engineering
Subject
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(authority = ETD-LCSH)
Topic
Amino acids
Subject
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(authority = ETD-LCSH)
Topic
Liver cells
Abstract
Extracorporeal bioartificial liver (BAL) devices, involving primary hepatocytes, represent a promising option to provide temporary support for patients with liver failure. Current use of BAL is primary challenged by development of techniques for long-term culture of hepatocytes during plasma exposure, as occurs during clinical application. Previous in vitro studies and mathematical modeling analysis have shown that supplementation of amino acids to the plasma enhances liver-specific functions and reduces lipid accumulation. However, further improvement would be enhanced greatly by development of a rational strategy to design the profile of amino acid supplementation and by better understanding of the metabolic objectives of hepatocytes, and how they vary as a function of amino acid supplementation.
In order to address these issues, a rational design approach was first developed using flux balance analysis (FBA) to determine a profile of amino acid supplementation to achieve a specific cellular objective (urea production) in cultured hepatocytes exposed to plasma. Experiments based on the designed supplementation showed that both urea and albumin production were increased compared with previously reported (empirical) amino acid supplementation. However, the experimental values did not match our theoretical prediction mainly due to the insufficient constraints imposed to the modeling.
In an attempt to improve the model accuracy, we incorporated pathway energy balance (PEB) constraints, and amino acids transport constraints. It is found that both PEB and transport constraints significantly reduce the feasible region of the flux space. Moreover, metabolic objective prediction (MOP) model reveals that hepatocytes respond to variations in available amino acid supplementation by changing their metabolic objectives and pathway utilization. In particular, the analysis shows that fatty acid oxidation is vital to reduce the rate of lipid accumulation and to increase liver-specific functions with amino acid supplementation.
This study leads to a better understanding of amino acid supplementation effects on hepatocytes during plasma exposure based on the integration of in vitro experiments and mathematical modeling. The approach enables the metabolic manipulation of hepatocytes with rationally designed amino acid supplementation to improve the targeted liver cell functionality and improve the long-term technique of hepatocytes applied for BAL devices.
In order to address these issues, a rational design approach was first developed using flux balance analysis (FBA) to determine a profile of amino acid supplementation to achieve a specific cellular objective (urea production) in cultured hepatocytes exposed to plasma. Experiments based on the designed supplementation showed that both urea and albumin production were increased compared with previously reported (empirical) amino acid supplementation. However, the experimental values did not match our theoretical prediction mainly due to the insufficient constraints imposed to the modeling.
In an attempt to improve the model accuracy, we incorporated pathway energy balance (PEB) constraints, and amino acids transport constraints. It is found that both PEB and transport constraints significantly reduce the feasible region of the flux space. Moreover, metabolic objective prediction (MOP) model reveals that hepatocytes respond to variations in available amino acid supplementation by changing their metabolic objectives and pathway utilization. In particular, the analysis shows that fatty acid oxidation is vital to reduce the rate of lipid accumulation and to increase liver-specific functions with amino acid supplementation.
This study leads to a better understanding of amino acid supplementation effects on hepatocytes during plasma exposure based on the integration of in vitro experiments and mathematical modeling. The approach enables the metabolic manipulation of hepatocytes with rationally designed amino acid supplementation to improve the targeted liver cell functionality and improve the long-term technique of hepatocytes applied for BAL devices.
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electronic resource
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xiii, 165 p. : ill.
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Ph.D.
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Includes bibliographical references (p. 154-164)
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by Hong Yang
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Yang
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Hong
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1976-
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Hong Yang
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Marianthi
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Marianthi G Ierapetritou
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Roth
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Charles
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Charles M Roth
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Androulakis
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Ioannis
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Ioannis P Androulakis
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Berthiaume
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Francois
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Francois Berthiaume
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Rutgers University
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Graduate School - New Brunswick
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2010
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2010-01
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xx
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Rutgers University Electronic Theses and Dissertations
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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doi:10.7282/T35M65VD
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ETD doctoral
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The author owns the copyright to this work.
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Copyright protected
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Open
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Permission or license
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Yang
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Hong
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2010-01-06 12:32:50
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Hong Yang
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Rutgers University. Graduate School - New Brunswick
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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