Human metabolic models and methods
First Claim
1. A computer readable medium or media having stored thereon computer-implemented instructions suitably programmed to cause a processor to perform the computer executable steps of:
- (a) providing a stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of Homo sapiens reactions between a plurality of Homo sapiens reactants,wherein each of said Homo sapiens reactions comprises a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, the stoichiometric coefficient relating said substrate and said product,wherein at least one of said Homo sapiens reactions is annotated to indicate an associated gene encoding a macromolecule that performs said reaction and wherein a plurality of chemically and electrochemically balanced Homo sapiens reactions are assigned to a plurality of different membranous compartments;
(b) providing a gene database comprising information characterizing said associated gene;
(c) providing a constraint set for said plurality of Homo sapiens reactions, the constraint set representing an upper or lower boundary condition of flux through each of the Homo sapiens reactions described in the stoichiometric matrix;
(d) defining an objective function to be a linear combination of fluxes through the Homo sapiens reactions described in the stoichiometric matrix that optimizes cell growth, reproduction, apoptosis, energy production, production of a particular compound, or a mechanical property;
(e) determining at least one steady state flux distribution for said plurality of chemically and electrochemically balanced Homo sapiens reactions across said plurality of different membranous compartments by (i) identifying a plurality of flux vectors that each satisfy a steady state condition for the stoichiometric matrix and satisfy the constraint set and (ii) identifying at least one linear combination of the flux vectors that minimizes or maximizes the objective function, wherein said at least one steady state flux distribution is predictive of a Homo sapiens physiological function at steady state; and
(f) providing output to a user of said at least one steady state flux distribution determined in step (e).
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Abstract
The invention provides in silico models for determining the physiological function of human cells, including human skeletal muscle cells. The models include a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, a constraint set for the plurality of Homo sapiens reactions, and commands for determining a distribution of flux through the reactions that is predictive of a Homo sapiens physiological function. A model of the invention can further include a gene database containing information characterizing the associated gene or genes. A regulated Homo sapiens reaction can be represented in a model of the invention by including a variable constraint for the regulated reaction. The invention further provides methods for making an in silico Homo sapiens model and methods for determining a Homo sapiens physiological function using a model of the invention.
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Citations
44 Claims
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1. A computer readable medium or media having stored thereon computer-implemented instructions suitably programmed to cause a processor to perform the computer executable steps of:
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(a) providing a stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of Homo sapiens reactions between a plurality of Homo sapiens reactants, wherein each of said Homo sapiens reactions comprises a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, the stoichiometric coefficient relating said substrate and said product, wherein at least one of said Homo sapiens reactions is annotated to indicate an associated gene encoding a macromolecule that performs said reaction and wherein a plurality of chemically and electrochemically balanced Homo sapiens reactions are assigned to a plurality of different membranous compartments; (b) providing a gene database comprising information characterizing said associated gene; (c) providing a constraint set for said plurality of Homo sapiens reactions, the constraint set representing an upper or lower boundary condition of flux through each of the Homo sapiens reactions described in the stoichiometric matrix; (d) defining an objective function to be a linear combination of fluxes through the Homo sapiens reactions described in the stoichiometric matrix that optimizes cell growth, reproduction, apoptosis, energy production, production of a particular compound, or a mechanical property; (e) determining at least one steady state flux distribution for said plurality of chemically and electrochemically balanced Homo sapiens reactions across said plurality of different membranous compartments by (i) identifying a plurality of flux vectors that each satisfy a steady state condition for the stoichiometric matrix and satisfy the constraint set and (ii) identifying at least one linear combination of the flux vectors that minimizes or maximizes the objective function, wherein said at least one steady state flux distribution is predictive of a Homo sapiens physiological function at steady state; and (f) providing output to a user of said at least one steady state flux distribution determined in step (e). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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16. A method for predicting a Homo sapiens physiological function, the method comprising:
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(a) providing a stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of Homo sapiens reactions between a plurality of Homo sapiens reactants, wherein each of said Homo sapiens reactions comprises a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, the stoichiometric coefficient relating said substrate and said product, wherein at least one of said Homo sapiens reactions is annotated to indicate an associated gene encoding a macromolecule that performs said reaction and wherein a plurality of chemically and electrochemically balanced Homo sapiens reactions are assigned to a plurality of different membranous compartments; (b) providing a gene database comprising information characterizing said associated gene; (c) providing a constraint set for said plurality of Homo sapiens reactions, the constraint set representing an upper or lower boundary condition of flux through each of the Homo sapiens reactions described in the stoichiometric matrix; (d) defining an objective function to be a linear combination of fluxes through the Homo sapiens reactions described in the stoichiometric matrix that optimizes cell growth, reproduction, apoptosis, energy production, production of a particular compound, or a mechanical property; (e) determining at least one steady state flux distribution for said plurality of chemically and electrochemically balanced Homo sapiens reactions across said plurality of different membranous compartments by (i) identifying a plurality of flux vectors that each satisfy a steady state condition for the stoichiometric matrix and satisfy the constrain set and (ii) identifying at least one linear combination of the flux vectors that minimizes or maximizes said objective function, wherein said at least one steady state flux distribution is predictive of a Homo sapiens physiological function; and (f) providing output to a user of said at least one steady state flux distribution determined ins step (e). - View Dependent Claims (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)
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Specification