improving boolean networks to model signaling pathways
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Improving Boolean Networks to Model Signaling Pathways
Bree AldridgeDiana Chai
BE.400 Term ProjectDecember 5, 2002
OutlineMotivation / Project GoalsIntroduction to Model SystemImplementation:
Boolean networkFuzzy network
Results / ConclusionsFuture Work
MotivationCellular states control behaviorQuantitative signaling and state data difficult to obtain Boolean-like networks:
Representative of how signaling networks process and transmit information“Simpler” than solving a huge system of ODEsTool to explore subnetwork interactions (crosstalk)Missing data holes may be filled in with intuition
Project GoalsExplore the use of Boolean-like networks to model signaling eventsDetermine level of abstraction to which Boolean-like networks are usefulMake qualitative predictions about important nodes in signaling pathways
Insulin
Insulin Receptor
Fibronectin
1
IRS1
FAK/Src
Grb2
Sos
Ras
Raf
Mek
Erk
P13K
Akt/PKB
DNA Synthesis
Model System
Asthagiri and Lauffenburger, 2001Anabi et al., 2001
Transient Behavior
Asthagiri and Lauffenburger, 2001
DNA Synthesis
Asthagiri et.al., 2000
Pure Boolean Model
Pure Boolean Output
Fuzzified ModelGo to Simulink:
Introduction to fuzzy logicMembership functionsRule based logicShow working model
Results : Time course
Results: DNA Synthesis
Take-home ResultsFuzzy logic networks are capable of capturing qualitative features of signaling networks (e.g. crosstalk) Easy to build despite lack of quantitative informationGood for testing hypotheses at higher level of abstraction than ODE-based models
Crosstalk Example
ConclusionsBoolean Networks are NOT sufficient to capture complex behaviors of signalling networks where behavior is not ALL or NONEFuzzy Logic Networks are best used at the qualitative prediction levelAlso good for exploring how subnetworks interactEspecially good for when data is lacking
Future WorkExplore the insulin signaling pathwayExplore different levels of crosstalkExplore sensitivity by changing membership functions and weighting rules
ReferencesAnnabi, Gautier, and Baron, Fed. Eur. Biochem. Soc., 507, 247-252 (2001)Assoian and Schwartz, Curr. Opin. Genet. Dev. 11, 48-53 (2001)Asthagiri and Lauffenburger, Biotechnol. Prog. 17, 227-239 (2001)Asthagiri, Reinhart, Horwitz, and Lauffenburger, J. Cell Sci., 113, 4499-4510 (2000)Asthagiri et.al., J. Biol. Chem., 274, 27119-27127 (1999)Eliceiri, Circ. Res., 89, 1104-1110 (2001)Giancotti and Ruoslahti, Science 285, 1028-1032 (1999)Guilherme , Torres, and Czech, J. Biol. Chem., 273, 22899-22903 (1998)Huang and Ferrell, PNAS, 93, 10078-10083 (1996)Huang and Ingber, Exper. Cell Res. 261, 91-103 (2000) Schwartz and Baron, Curr. Opin. Cell Biol. 11, 197-202 (1999)Vuori and Ruoslahti, Science 266, 1576-1578 (1994)
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