A growing number of reconstructed metabolic reaction networks have appeared in recent years. Such reconstruction can be converted into a mathematical format that in turn can be used to analyze the properties of the networks. Genome-scale analysis of network properties leads to understanding of their normal physiological functions and malfunction leading to pathophysiological states. The first part of this R01 program was focused on the analysis of possible steady state flux distributions of metabolic networks using extreme pathways. This analysis has proven useful for a number of purposes but is limited in scope. Fortunately, we have found random sampling of the solution space to be a viable and useful alternative to extreme pathways. During the second part of this program we propose to 1) develop uniform randomized sampling of the feasible steady state solution spaces, 2) to apply these algorithms to a series of biological and medical examples, and 3) develop time-scale decomposition of large- scale kinetic models. If the proposed program is successfully executed it will advance the state of the art of building genome-scale models to account for concentrations and to develop first-pass network-scale dynamic models. The availability of such genome-scale models would expand their scope of predictions and thus their applications to various biological and health care issues.

Public Health Relevance

Project Narrative Public investment in DNA sequencing has led to the sequencing of entire genomes of a growing number of organisms. Scientists have determined how to assemble the information found in genomic sequences, along with data from the scientific literature, into the biochemical reaction networks that underlie cellular functions. This process is particularly advanced for metabolism;this proposal is focused on the mathematical description and analysis of metabolic functions in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068837-08
Application #
8244434
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Gerratana, Barbara
Project Start
2003-07-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$321,022
Indirect Cost
$113,241
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Thomas, Alex; Rahmanian, Sorena; Bordbar, Aarash et al. (2014) Network reconstruction of platelet metabolism identifies metabolic signature for aspirin resistance. Sci Rep 4:3925
Bordbar, Aarash; Monk, Jonathan M; King, Zachary A et al. (2014) Constraint-based models predict metabolic and associated cellular functions. Nat Rev Genet 15:107-20
Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E et al. (2014) Minimal metabolic pathway structure is consistent with associated biomolecular interactions. Mol Syst Biol 10:737
Chang, Roger L; Xie, Lei; Bourne, Philip E et al. (2013) Antibacterial mechanisms identified through structural systems pharmacology. BMC Syst Biol 7:102
Bordbar, A; Palsson, B O (2012) Using the reconstructed genome-scale human metabolic network to study physiology and pathology. J Intern Med 271:131-41
Schellenberger, Jan; Zielinski, Daniel C; Choi, Wing et al. (2012) Predicting outcomes of steady-state ýýýýC isotope tracing experiments using Monte Carlo sampling. BMC Syst Biol 6:9
Schellenberger, Jan; Que, Richard; Fleming, Ronan M T et al. (2011) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0. Nat Protoc 6:1290-307
Schellenberger, Jan; Lewis, Nathan E; Palsson, Bernhard O (2011) Elimination of thermodynamically infeasible loops in steady-state metabolic models. Biophys J 100:544-53
Bordbar, Aarash; Jamshidi, Neema; Palsson, Bernhard O (2011) iAB-RBC-283: A proteomically derived knowledge-base of erythrocyte metabolism that can be used to simulate its physiological and patho-physiological states. BMC Syst Biol 5:110
Bordbar, Aarash; Lewis, Nathan E; Schellenberger, Jan et al. (2010) Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions. Mol Syst Biol 6:422

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