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Methods and Systems to Identify Operational Reaction Pathways

a technology of operational reaction and method, applied in the field of in silico model organism construction, can solve the problems of difficult to predict a priori the effect of a single gene or gene product change, or the effect of a drug or an environmental factor, on cellular behavior, and current approaches to the development of compounds and processes used in these directions do not take into account the level of accuracy needed for perturbation effect on cellular behavior,

Inactive Publication Date: 2010-12-16
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides methods for identifying and refining reaction pathways in a biosystem, as well as diagnosing genetic polymorphism-mediated pathologies. These methods involve comparing systemic and phenomenological reaction pathways, and modifying the structure of the biosystem's mathematical representation to minimize behavioral differences. The consistency measure between reaction categories in the first reaction network and elements in the second reaction network indicates the validity of the first reaction network. The sensitivity of the reaction network to a biochemical or physiological condition in a stressed physiological state indicates the phenotypic consequence of the genetic polymorphism-mediated pathology.

Problems solved by technology

Such changes or perturbations can lead to both desirable and undesirable effects in any therapeutic, industrial or agricultural process involving living cells.
However, current approaches to therapeutic, industrial and agricultural development for compounds and processes used therein do not take into account the effect of perturbations on cellular behavior at the level of accuracy needed for efficient and economical production of products.
Because of this interconnectivity, it is difficult to predict a priori the effect of a change in a single gene or gene product, or the effect of a drug or an environmental factor, on cellular behavior.

Method used

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  • Methods and Systems to Identify Operational Reaction Pathways
  • Methods and Systems to Identify Operational Reaction Pathways
  • Methods and Systems to Identify Operational Reaction Pathways

Examples

Experimental program
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Effect test

example i

Decomposing a Set of Phenomenological Flux Distributions for the E. coli Core Metabolic Network in Order to Identify Operational Extreme Pathways

[0140]This example shows how a set of phenomenological pathways (flux distributions) can be decomposed into dominant modes these modes can be compared with a set of systemic pathways (extreme pathways) to identify operational reaction pathways of a metabolic reaction network (E. coli core metabolism).

[0141]An in silico-generated metabolic flux profile of core metabolism in E. coli was prepared. The reactions were taken from table 6.3 of Schilling, “On Systems Biology and the Pathway Analysis of Metabolic Networks,” Department of Bioengineering, University of California, San Diego: La Jolla. p. 198-241 (2000), with the exception that reaction pntAB was not included, and instead of T3P2 in reaction tktA2, T3P1 was used. The reaction list is tabulated in Table 1.

[0142]The flux profile, which is the input matrix for Singular Value Decomposit...

example ii

Identifying Human Red Blood Cell Extreme Pathways Corresponding to Physiologically Relevant Flux Distributions

[0151]This example shows how a set of phenomenological pathways (flux distributions) generated by a kinetic model can be compared with the modal decomposition of a set of systemic pathways (extreme pathways) to identify dominant regulatory modes of a metabolic reaction network (human red blood cell metabolism).

[0152]The extreme pathways of the red blood cell (RBC) metabolic network have been computed (Wiback, S. J. & Palsson, B. O. Biophysical Journal 83, 808-818 (2002)). Here, SVD analysis was applied to the extreme pathway matrix, P, formed by these pathways. A full kinetic model of the entire metabolic network of the RBC has been developed (Jamshidi, N., Edwards, J. S., Fahland, T., Church, G. M., Palsson, B. O. Bioinformatics 17, 286-7 (2001); Joshi, A. & Palsson, B. O. Journal of Theoretical Biology 141, 515-28 (1991)), and was used to generate flux vectors (v) for ph...

example iii

In Silico Assessment of the Phenotypic Consequences of Red Blood Cell Single Nucleotide Polymorphisms

[0171]The following example illustrates the application of the described methods to analysis of phenomenological pathways defined through pathological data.

[0172]The Human Genome Project (HGP) is now essentially complete. One result of the HGP is the definition of single nucleotide polymorphisms (SNPs) and their effects on the development of human disease. Although the number of SNPs in the human genome is expected to be a few million, it is estimated that only 100,000 to 200,000 will effectively define a unique human genotype. A subset of these SNPs are believed to be “informative” with respect to human disease (Syvanen, A., 2001. Accessing genetic variation: Genotyping single nucleotide polymorphisms. Nat Rev Genet 2: 930-942). Many of these SNPs will fall into coding regions while others will be found in regulatory regions. The human genotype-phenotype relationship is very comple...

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Abstract

The present invention provides a method for identifying an operational reaction pathway of a biosystem. The method includes (a) providing a set of systemic reaction pathways through a reaction network representing said biosystem; (b) providing a set of phenomenological reaction pathways of said biosystem, and (c) comparing said set of systemic reaction pathways with said set of phenomenological reaction pathways, wherein a pathway common to said sets is an operational reaction pathway of said biosystem. Also described is a method of refining a biosystem reaction network; a method of reconciling biosystem data sets; a method of determining the effect of a genetic polymorphism on whole cell function; and a method of diagnosing a genetic polymorphism-mediated pathology.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. application Ser. No. 10 / 367,248 filed Feb. 14, 2003, now issued as U.S. Pat. No. 7,734,420; which claims the benefit under 35 USC §119(e) to U.S. application Ser. No. 60 / 419,023 filed Oct. 15, 2002, now expired. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]This invention relates generally to the construction of in silico model organisms and, more specifically, methods and systems specifying operational reaction pathways and for the generation of optimal in silico models of actual organisms.[0004]1. Background Information[0005]Therapeutic agents, including drugs and gene-based agents, are being rapidly developed by the pharmaceutical industry with the goal of preventing or treating human disease. Dietary supplements, including he...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68G01N33/50G16B5/10G16B25/10G16B40/30
CPCG01N33/5005G16B40/00G16B25/00G16B5/00G16B40/30G16B25/10G16B5/10
Inventor PALSSON, BERNARD O.COVERT, MARKUS W.HERRGARD, MARKUS
Owner RGT UNIV OF CALIFORNIA
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