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what_can_do_hipathia_for_you [2020/01/27 20:20] – [Variant interpreter] krianwhat_can_do_hipathia_for_you [2021/01/05 15:48] – [Variant interpreter] krian
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 Mechanistic models offer a realistic framework to understand how signal transduction depends on changes in the expression of genes involved in signaling pathway circuits (see [[http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=14107&pubmed-linkout=1|Hidalgo et al., 2017]]). Interestingly, cell signaling circuits trigger relevant cell functionalities (e.g., proliferation, cell death, metabolic changes, etc.), which virtually allows to estimate not only **signaling activity profiles** but also a cell **functional activity profiles**, from **transcriptional profiles**. Moreover, a mechanistic model allows predicting the effect of interventions (gene knock-outs, drugs, etc.) over a given sample, opening the door to multiple applications for **research** or **therapeutic** purposes. Mechanistic models offer a realistic framework to understand how signal transduction depends on changes in the expression of genes involved in signaling pathway circuits (see [[http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=14107&pubmed-linkout=1|Hidalgo et al., 2017]]). Interestingly, cell signaling circuits trigger relevant cell functionalities (e.g., proliferation, cell death, metabolic changes, etc.), which virtually allows to estimate not only **signaling activity profiles** but also a cell **functional activity profiles**, from **transcriptional profiles**. Moreover, a mechanistic model allows predicting the effect of interventions (gene knock-outs, drugs, etc.) over a given sample, opening the door to multiple applications for **research** or **therapeutic** purposes.
-  +===== Hipathia mechanism ===== 
 +HiPathia retrieves pathway information from [[https://www.kegg.jp/kegg/pathway.html|KEGG database]]. KEGG pathway database is a collection of manually drawn pathway maps representing the knowledge on the molecular interaction, reaction and relation networks. 
 + 
 +The purpose of a signalling pathway is to activate a cellular function carried out by an effector protein. This activation is given as a result of a cascade of protein interactions triggered by a stimulus captured by a receptor protein.  
 +{{ ::kegg.png?nolink |}} 
 +In Hipathia, the activation values for the different effector circuit within a signalling pathway are calculated separately. One example might be the red-highlighted circuit on the figure below. These method was chosen because of the fact that many pathways are multifunctional and often trigger opposite functions (e.g. depending the receptor and the effector proteins involved in the transduction of the signal, the apoptosis pathway may trigger survival or cell death). 
 +{{ ::circuit.png?nolink |}} 
 +Once an "effector circuit" topology is known, Hipathia uses gene expression values as proxies of protein presence values, and consequently of potential protein activation values. Two types of nodes can be found: plain nodes and complex nodes. The first ones, are nodes which function (passing the signal form the previous node to the next one) is carried out by only one protein. However the functions of these nodes may be accomplished by more than one protein. In such case the node value is summarized as the percentile 90 of the values of the proteins contained in it. On the complex nodes, it is necessary the presence of more than one protein to pass the signal through. The minimum value of the proteins contained (the limiting component of the complex), is taken as the node activity value. 
 + 
 +In order to calculate the circuit signal, once the node activity values have been estimated, we assume an incoming signal value of 1 in the input nodes (stimuli-receptor proteins) of any circuit. Then, the signal is propagated to the following nodes as shown in the image above until it reaches its effector node. This is going to be the values that will be taken as the activation value for each "effector circuit". 
 + {{ ::path_mechanism.png?nolink |}} 
 +Finally, Hipathia also calculates the activation state of some molecular functions by looking at the functions annotated for the effector proteins in which the "effector circuit" finishes. With Hipathia's method it is possible to obtain an individual activation value of the different functions for each. Therefore it's also possible to infer which functions have different activation levels in the groups that are being compared. This feature is implemented for the annotations of the Uniprot database and Gene Ontology.  
 + 
 +This video present a simple simulation of how Hipathia model calculates the propagated signal throw a signaling circuit: 
 +{{ ::demoalgo.gif?nolink |}} 
 + 
 +===== HiPathia modules ===== 
 The HiPathia web server integrates four different pathway analysis modules: The HiPathia web server integrates four different pathway analysis modules:
   * **Differential signaling**   * **Differential signaling**
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 See more about the [[Perturbation effect|Perturbation effect]] tool. See more about the [[Perturbation effect|Perturbation effect]] tool.
  
-===== Variant interpreter =====+==== Variant interpreter ====
  
 This tool provides an estimation of the potential impact of genomic variation over cell signaling and consequently on cell functionality.  This tool provides an estimation of the potential impact of genomic variation over cell signaling and consequently on cell functionality. 
what_can_do_hipathia_for_you.txt · Last modified: 2021/01/05 15:49 by krian