Using Pathway Logic to Integrate Signal Transduction and Gene Expression Data

Pathway Logic (http://pl.csl.sri.com/) is an approach to the modeling
and analysis of molecular and cellular processes based on rewriting
logic. Pathway Logic (PL) models reflect the ways that biologists
think about problems using informal models.  They are curated from the
literature, and written and analyzed using Maude, a
rewriting-logic-based formalism (http://maude.cs.uiuc.edu). A Pathway
Logic knowledge base includes data types representing cellular
components such as proteins, small molecules, complexes,
compartments/locations protein state, and post-translational
modifications. Modifications can be abstract, just specifying being
activated, bound, or phosphorylated, or more specific, for example,
phosphorylation at a particular site. Collections of entities, treated
as `liquid' mixtures, are represented as multisets (unordered
collections). Rewrite rules describe the behavior of proteins and
other components depending on modification state and biological
context. Each rule represents a step in a biological process such as
metabolism or intra/inter- cellular signaling. A specific model is
assembled by specifying an initial state (called a dish): the cells,
their components, and entities such as ligands in the supernatant.

The Pathway Logic Assistant (PLA) provides an interactive visual
representation of PL models. Using PLA one can

   display the network of signaling reactions for a specified model; 

   formulate and submit queries to find pathways, for example 
      activating one protein without activating a second protein, or
       exhibiting a phenotype signature such as apoptosis;

   compare two pathways; 

   find single or double knockouts---individual or pairs
       of proteins whose omission prevents reaching a specified state;

   compute and display the subnet relevant to one or more proteins; and

   visualize gene expression data in the context of a network 
      (by coloring the coded proteins according to expression level).
  
The poster will illustrate this approach in the context of a model of
TLR signaling.

In this PL model of TLR signaling, one can show that the Interferon
beta gene can not be turned on by activating TLR2. In fact there is no
pathway that jointly achieves the goals of activating TLR2 and turning
on Ifnbgene. On the surface, this is an artifact of the way the model
treats competition of TLR2 and TLR4 for Lps. But it suggests
investigation of this competition. Does one of the receptors dominate?
What if one is highly over expressed and not the other? Activation of
TLR2 does lead to the Il6 gene being turned on.