13 research outputs found
Biological control networks suggest the use of biomimetic sets for combinatorial therapies
Cells are regulated by networks of controllers having many targets, and
targets affected by many controllers, but these "many-to-many" combinatorial
control systems are poorly understood. Here we analyze distinct cellular
networks (transcription factors, microRNAs, and protein kinases) and a
drug-target network. Certain network properties seem universal across systems
and species, suggesting the existence of common control strategies in biology.
The number of controllers is ~8% of targets and the density of links is 2.5%
\pm 1.2%. Links per node are predominantly exponentially distributed, implying
conservation of the average, which we explain using a mathematical model of
robustness in control networks. These findings suggest that optimal
pharmacological strategies may benefit from a similar, many-to-many
combinatorial structure, and molecular tools are available to test this
approach.Comment: 33 page
Metabolism as means for hypoxia adaptation: metabolic profiling and flux balance analysis
BACKGROUND: Cellular hypoxia is a component of many diseases, but mechanisms of global hypoxic adaptation and resistance are not completely understood. Previously, a population of Drosophila flies was experimentally selected over several generations to survive a chronically hypoxic environment. NMR-based metabolomics, combined with flux-balance simulations of genome-scale metabolic networks, can generate specific hypotheses for global reaction fluxes within the cell. We applied these techniques to compare metabolic activity during acute hypoxia in muscle tissue of adapted versus "naïve" control flies. RESULTS: Metabolic profiles were gathered for adapted and control flies after exposure to acute hypoxia using (1)H NMR spectroscopy. Principal Component Analysis suggested that the adapted flies are tuned to survive a specific oxygen level. Adapted flies better tolerate acute hypoxic stress, and we explored the mechanisms of this tolerance using a flux-balance model of central metabolism. In the model, adapted flies produced more ATP per glucose and created fewer protons than control flies, had lower pyruvate carboxylase flux, and had greater usage of Complex I over Complex II. CONCLUSION: We suggest a network-level hypothesis of metabolic regulation in hypoxia-adapted flies, in which lower baseline rates of biosynthesis in adapted flies draws less anaplerotic flux, resulting in lower rates of glycolysis, less acidosis, and more efficient use of substrate during acute hypoxic stress. In addition we suggest new specific hypothesis, which were found to be consistent with existing data
Metabolomic and flux-balance analysis of age-related decline of hypoxia tolerance in Drosophila muscle tissue
The fruit fly D. melanogaster is increasingly used as a model organism for
studying acute hypoxia tolerance and for studying aging, but the interactions
between these two factors are not well known. Here we show that hypoxia
tolerance degrades with age in post-hypoxic recovery of whole-body movement,
heart rate and ATP content. We previously used 1H NMR metabolomics and a
constraint-based model of ATP-generating metabolism to discover the end
products of hypoxic metabolism in flies and generate hypotheses for the
biological mechanisms. We expand the reactions in the model using tissue- and
age-specific microarray data from the literature, and then examine metabolomic
profiles of thoraxes after 4 hours at 0.5% O2 and after 5 minutes of recovery
in 40- versus 3-day-old flies. Model simulations were constrained to fluxes
calculated from these data. Simulations suggest that the decreased ATP
production during reoxygenation seen in aging flies can be attributed to
reduced recovery of mitochondrial respiration pathways and concomitant
over-dependence on the acetate production pathway as an energy source.Comment: 30 page
Search algorithms as a framework for the optimization of drug combinations
Combination therapies are often needed for effective clinical outcomes in the
management of complex diseases, but presently they are generally based on
empirical clinical experience. Here we suggest a novel application of search
algorithms, originally developed for digital communication, modified to
optimize combinations of therapeutic interventions. In biological experiments
measuring the restoration of the decline with age in heart function and
exercise capacity in Drosophila melanogaster, we found that search algorithms
correctly identified optimal combinations of four drugs with only one third of
the tests performed in a fully factorial search. In experiments identifying
combinations of three doses of up to six drugs for selective killing of human
cancer cells, search algorithms resulted in a highly significant enrichment of
selective combinations compared with random searches. In simulations using a
network model of cell death, we found that the search algorithms identified the
optimal combinations of 6-9 interventions in 80-90% of tests, compared with
15-30% for an equivalent random search. These findings suggest that modified
search algorithms from information theory have the potential to enhance the
discovery of novel therapeutic drug combinations. This report also helps to
frame a biomedical problem that will benefit from an interdisciplinary effort
and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio
Results of flux-balance analysis on the model of ATP-generating metabolism
<p><b>Copyright information:</b></p><p>Taken from "Flexibility in energy metabolism supports hypoxia tolerance in flight muscle: metabolomic and computational systems analysis"</p><p></p><p>Molecular Systems Biology 2007;3():99-99.</p><p>Published online 17 Apr 2007</p><p>PMCID:PMC1865581.</p><p>Copyright © 2007, EMBO and Nature Publishing Group</p> () Proton production increases but then levels off at low oxygen levels as pyruvate begins to be fermented to alanine, acetate, and lactate. Glucose uptake is decreased during restricted oxygen. () When pyruvate is only allowed to be converted to lactate (pseudo-mammalian), proton production is much higher and glucose uptake remains constant during hypoxia, whereas () ATP production remains the same or better. Abbreviations: ac: acetate accumulation; ala: alanine accumulation; atp: ATP production; CO: CO production; glc: glucose uptake; h: proton production and lac: lactate accumulation
Mathematical model of the number and robustness of output states in a bipartite control network.
<p>We explored the dependence of these quantities on the average incoming links per target <i>in></i>, number of controllers <i>M</i>, number of targets <i>N</i>, and mutation rate (or links deleted as a fraction of <i>N</i>, robustness equation only). Shown are averages of 1000 numerical simulations with <i>M</i> = <i>N</i> = 10, and  = 0.1. Analytical solutions for robustness and unique output states using the OR rule were also derived and plotted (lower right), and found to be identical or a close approximation to simulations, respectively (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029374#s4" target="_blank">Methods</a>). Both quantities were independent of <i>N</i> in numerical and analytical solutions. These results suggest that marginal utility to robustness of increasing <i>in></i> shrinks rapidly above ∼5, while at the same time incurring a cost on the degree of freedom of output states.</p