PathwayLogic通路逻辑

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Pathway Logic,Symbolic Analysis of Biological Signaling,Presented by Geoffrey,Introduction,Tremendous growth of genomic sequence information combined with technological advances in the analysis of gene expression has revolutionized research in biology and biomedicine,Investigation of signaling and metabolic pathways would benefit greatly from the use of predictive models,Although these pathways are complex,fundamental concepts that stemmed from contemporary research indicates that they are also amenable to analysis via computational methods.E.g.most signaling pathways involved hierarchical assembly in space and time of multi-protein complexes that regulate the flow of information via stimulation or inhibition,Introduction,Various models have been proposed that incorporates quantitative information such as rate and/or concentration information,However they are limited due to the difficulty in obtaining the relevant parameters e.g.Michaelis constant etc.as well as stochastic features of signaling molecules,Hence another way to look at such pathways is by the logic of signal,e.g.use of,-calculus to represent and forward simulate signaling pathway,In this paper,we will look at the development of logical models based on the application of formal methods tools to mammalian signaling pathways,Levels of Abstraction,Continuous Abstraction,Involves continuous mathematics such as differential equations and are analyzed using sophisticated numerical computational packages,However the complexity of biological processes limits its accuracy and effective description,Discrete Abstraction,Natural processes are described by purely symbolic expressions,Applicable to less predictable phenomena such as biological signaling processes(as we shall see later on),Pathway Logic,Pathway Logic,an algebraic structure enabling the symbolic analysis of biological signaling pathways,It uses,rewriting theories,to formalize the informal models that biologists use to describe processes,Advantages of using Pathway Logic:,Can include both facts and principles relating and categorizing data elements and processes,Allows data to be interpreted,combined and queried in the context of,biological knowledge,Allows models with various levels of details,Dynamically generate pathways using search and model-checking,Transformation to,Petri nets,for analysis and visualization,Roadmap views of dynamically generated pathways,Pathway logic algebra can be written in the,Maude,executable specification language,Pathway Logic Example,As an example,we will consider a major receptor-mediated pathway in mammalian cells,focusing on the,Epidermal Growth Factor Receptor,Fragment of the mammalian EGFR system illustrating the activation of a downstream mitogenic signaling pathway involving the gene for the autocrine EGRF ligand TGFa,Biological Sorts and Elements,The basic declaration of types in Pathway Logic(or Maude)is by using the keyword,sorts,and,subsorts,Constants and operators are defined using the keyword,ops,sorts Protein Chemical Thing.,subsorts Protein Chemical Protein.,ops Ca+:-Chemical,EGRF,EGF,PIP3,Pdk1,PKCe are operations that maps from empty to the Protein sort,indicating that they are constants of Protein,Thing is a sort that encompasses Protein and Chemical,something like a super class,Protein Modification,Pathway Logic allows a comprehensive algebra of protein modification.The example below shows a small part of its declaration and specification in Maude,sorts Modification ModSet.,subsort Modification Modification.,op none:-ModSet.,op _ _:ModSet ModSet-ModSet assoc comm id:none.,op _-_:Protein ModSet-Protein right id:none.,This line denotes a list of modification sets that has elements that are associative,commutative and has none as its identity element,Sets of modifications are applied to proteins using the operator _-_ for example EGRF act represents the activated form of EGRF,Protein Association,Signaling proteins commonly associate to form functional complexes.This is represented using Maude by the following specification code,sort Complex.,subsort Complex Complex comm,Hence multi-protein complexes can be specified from proteins and other things by using the“:operator,And example would be the inhibitory complex,(IqGap1:(Ecadherin:bCatenin),Protein Compartmentalization,In eukaryotic cells(i.e.cells with nucleus)proteins and other molecules exist in complex mixtures that are compartmentalized.,They are represented algebraically by the following declarations,Sorts Soup Enclosure MemType.,Subsort Thing Soup.,Op _ _:Soup Soup-Soup assoc comm id:empty.,Ops CM NM:-MemType.,Op _|_:MemType Soup Soup-Enclosure.,The type of membrane,Contents of the membrane,Contents of the membrane,Protein Compartmentalization,An enclosure has its own membrane part and internal,each with its own constituent soup,For example,CM|cm:Soup PIP3 Pdk1-act cyto:Soup