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US 8,301,393 B2Granted
Methods and systems for genome-scale kinetic modeling
AssigneeThe Regents of the University of California
InventorsBernhard O. Palsson, Neema Jamshidi
Life of this patent
Estimating the term…
Abstract
Embodiments of the present invention generally relate to the construction, analysis, and characterization of dynamical states of biological networks at the cellular level. Methods are provided for analyzing the dynamical states by constructing matrices using high-throughput data types, such as fluxomic, metabolomic, and proteomic data. Some embodiments relate to an individual, while others relate to a plurality of individuals.
Claims51
A computer-implemented method for developing data-driven dynamic models of biological networks comprising:
- providing, at a computer system, a data structure relating a plurality of biological network reactants to a plurality of biological network reactions, the plurality of biological network reactions comprising one or more flux distributions, wherein each of the biological network reactions comprises one or more biological network reactants identified as a substrate of the reaction, one or more biological network reactants identified as a product of the biological network reaction and a stoichiometric coefficient relating the substrate and the product;
- providing, at a computer system, a constraint set for the plurality of biological network reactions;
- providing, at a computer system, a constraint set for a plurality of concentrations associated with the plurality of biological network reactions;
- providing, at a computer system, a constraint set for a plurality of kinetic constants associated with the plurality of biological network reactions;
- providing, at a computer system, a constraint set for a plurality of equilibrium constants associated with the plurality of biological network reactions;
- integrating, at a computer system, the sets of constraints, thereby forming stoichiometric, gradient, and Jacobian matrices;
- providing, at a computer system, an objective function;
- and
- predicting, at a computer system, a physiological function related to at least one of the biological networks by determining using the computer system at least one flux distribution, from the one or more flux distributions, that minimizes or maximizes the objective function when at least one constraint set from the sets of constraints is applied to the data structure.
6 more elements
A computer-implemented method for the analysis of disease states due to genetic and/or environmental influences comprising:
- providing, at a computer system, a data structure relating a plurality of reactants to a plurality of reactions, the plurality of reactions comprising one or more flux distributions, wherein each of the reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;
- providing, at a computer system, a constraint set for the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of concentrations associated with the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of kinetic constants associated with the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of equilibrium constants associated with the plurality of reactions;
- integrating, at a computer system, the sets of constraints, thereby forming stoichiometric, gradient, and Jacobian matrices;
- providing, at a computer system, an objective function;
- modifying, at a system, at least one of the reaction constraint set, the concentration constraint set, the kinetic constant set and the equilibrium constant set based at least partly on genetic variations;
- modifying, at a computer system, at least one of the reaction constraint set, the concentration constraint set, the constraint set for a plurality of kinetic constants and the set for a plurality of equilibrium constants based at least partly on altered environmental conditions;
- and
- predicting, using a computer system, a physiological function related to one of the disease states by determining at least one flux distribution, from the one or more flux distributions, that minimizes or maximizes the objective function when at least one constraint set from the sets of constraints is applied to the data structure.
8 more elements
A computer-implemented method for the analysis of therapies for drug treatments, the method comprising:
- providing, at a computer system, a data structure relating a plurality of reactants to a plurality of reactions, the plurality of reactions comprising one or more flux distributions, wherein each of the reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;
- providing, at a computer system, a constraint set for the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of concentrations associated with the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of kinetic constants associated with the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of equilibrium constants associated with the plurality of reactions;
- integrating, at a computer system, the sets of constraints, thereby forming stoichiometric, gradient, and Jacobian matrices;
- providing, at a computer system, an objective function;
- providing, at a computer system, an experimental constraint set for the plurality of reactions, concentrations, or kinetic constants for an altered set of constraints due to a treatment with a drug or chemical agent;
- and
- predicting, at a computer system, a physiological function related to the drug treatment by determining at least one flux distribution, from the one or more flux distributions, that minimizes or maximizes the objective function when a constraint set is applied to the data structure.
7 more elements
A computer-implemented method for accounting for small metabolite regulation comprising:
- providing, at a computer system, a data structure relating a plurality of reactants to a plurality of reactions, the plurality of reactions comprising one or more flux distributions, wherein each of the reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product, in which the reactions may reflect regulatory processes;
- providing, at a computer system, a constraint set for the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of concentrations associated with the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of kinetic constants associated with the plurality of reactions;
- providing, at a computer system, a constraint set for a plurality of equilibrium constants associated with the plurality of reactions;
- integrating, at a computer system, the sets of constraints, thereby forming stoichiometric, gradient, and Jacobian matrices;
- providing, at a computer system, an objective function;
- and
- predicting, at a computer system, a physiological function related to the small metabolite regulation by determining using the computer system at least one flux distribution, from the one or more flux distributions, that minimizes or maximizes the objective function when at least one constraint set from the sets of constraints is applied to the data structure.
6 more elements
A computer-implemented method for determining one or more parameters to characterize different functional states comprising:
- analyzing, at a computer system, a network function;
- determining, at a computer system, time scales of interest;
- and
- identifying, at a computer system, parameters that describe the network function based on at least one of a stoichiometric, gradient, or Jacobian matrix, the stoichiometric, gradient, or Jacobian matrix formed, at least in part, based on an integration of a set of constraints, wherein the constraint set comprises a plurality of mass action relationships which also incorporate metabolomic data and thermodynamic data.
1 more element
A non-transitory computer readable medium containing software embedded in the computer readable medium, the software configured such that, when executed, it causes one or more computer systems to perform the acts of:
- receiving a data structure relating a plurality of reactants to a plurality of reactions, the plurality of reactions comprising one or more flux distributions, wherein each of the reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;
- receiving a constraint set for the plurality of reactions;
- receiving a constraint set for a plurality of concentrations associated with the plurality of reactions;
- receiving a constraint set for a plurality of kinetic constants associated with the plurality of reactions;
- receiving a constraint set for a plurality of equilibrium constants associated with the plurality of reactions;
- integrating the sets of constraints, thereby forming stoichiometric, gradient, and Jacobian matrices;
- receiving an objective function;
- and
- predicting a physiological function by determining at least one flux distribution, from the one or more flux distributions, that minimizes or maximizes the objective function when the constraint set from the sets of constraints is applied to the data structure.
6 more elements
A computer implemented system comprising:
- a computing environment;
- a storage in data communication with the computing environment and configured to store data structure relating a plurality of reactants to a plurality of reactions;
- and
- a software program operating on the computing environment and configured to:
- provide the data structure relating the plurality of reactants to the plurality of reactions, the plurality of reactions comprising one or more flux distributions, wherein each of the reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;
- provide a constraint set for the plurality of reactions;
- provide a constraint set for a plurality of concentrations associated with the plurality of reactions;
- provide a constraint set for a plurality of kinetic constants associated with the plurality of reactions;
- provide a constraint set for a plurality of equilibrium constants associated with the plurality of reactions;
- integrate the sets of constraints, thereby forming a stoichiometric, gradient, and Jacobian matrices;
- provide an objective function;
- and
- predict a physiological function by determining at least one flux distribution, from the one or more flux distributions, that minimizes or maximizes the objective function when the constraint set from the sets of constraints is applied to the data structure.
10 more elements
A system comprising:
- means for providing a data structure relating a plurality of reactants to a plurality of reactions, the pluralality of biological network reactions comprising one or more flux distributions, wherein each of the reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;
- means for providing a constraint set for the plurality of reactions;
- means for providing a constraint set for a plurality of concentrations associated with the plurality of reactions;
- means for providing a constraint set for a plurality of kinetic constants associated with the plurality of reactions;
- means for providing a constraint set for a plurality of equilibrium constants associated with the plurality of reactions;
- means for integrating the sets of constraints, thereby forming stoichiometric, gradient, and Jacobian matrices;
- means for providing an objective function;
- and
- means for predicting a physiological function based on the objective function and at least one of the constraint sets.
6 more elements
A computer-implemented method for predicting a physiological function comprising:
- providing, at a computer system, a data structure relating a plurality of H. sapiens reactants to a plurality of H. sapiens reactions, wherein said H. sapiens reactions comprise one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;
- providing, at a computer system, a constraint set for the plurality of H. sapiens reactions, wherein the constraint set comprises a plurality of mass action relationships which also incorporate metabolomic data and thermodynamic data;
- providing, at a computer system, an objective function;
- determining, at a computer system, at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, thereby predicting a H. sapiens physiological function;
- and
- integrating, at a computer system, the set of constraints to form at least a stoichiometric, gradient, or Jacobian matrix.
3 more elements
Dependencies are inferred from the claim text.