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Summary

Many AOPs are described for specific cellular or tissue contexts.  For improved integration of BEL with this feature of AOPs, tractable BEL solutions are needed to indicate these contexts at the node level.  Node-level descriptors will immediately convey the specific context of a particular model.

Details

Many AOPs describe key molecular events that occur in specific locations: whether a cell type, intracellular location, or tissue/organ.  The location of the event is important information in an AOP and needs to be captured in a form that is useful and understandable, as well as tractable in BEL.

Many molecular events can happen canonically in a variety of cellular contexts.  However, in an AOP we are usually interested specifically in those events that are happening in one particular context.  An important aspect of AOPs is having evidence something is occurring, so we’d need to be able to script canonical events in the tissue needed for the AOP.  We currently capture this type of information in the annotation, but for AOP visualization and human interpretation it would be useful to display in the node/model as well.  In this regard, we propose adding the gross cellular/tissue/organ context to the “loc” modifier.  Several realizations of this thought are proposed below.  As the working example, we will use a ready for comment AOP from the AOPwiki, “PPARγ activation leading to impaired fertility in adult female”  (see AOPwiki).

 

 

 

From this AOP, it is important to note we would need to capture where the PPAR activation is occurring (Granulosa cells) and where an important downstream biomarker may be located (Circulation) and what type of individual this is occurring in (Females, specifically from the evidence in this AOP, rat).   A specific cell type/tissue namespace will need to be chosen (potentially MESH-based).

 

Option 1:  Make the cellular context simply a modifier of the node as for subcellular localization

The only drawbacks are the possibility of needing to specify different types of relationships at the same time, i.e., establishing sub-cellular location on top of the gross cell or tissue location, and lack of sufficient tissue-specific knowledge for model building and/or scoring.  At the very least, we would have to make sure BEL could handle multiple “loc” levels.

tscript(a(RGD: Pparg), loc(namespace: Granulosa cells)) decreases a(RGD: Cyp19a1, loc(namespace: Granulosa cells))

a(RGD: Cyp19a1, loc(namespace: Granulosa cells)) increases a(CHEBI: estradiol, loc(namespace: Granulosa cells))

tloc(a(CHEBI: estradiol)), fromLoc(namespace: Granulosa Cell), toLoc(namespace: blood)

a(CHEBI: estradiol, loc(namespace: blood)) increases bp(MESHPP: ”Menstrual Cycle”)

 

 

Option 2:  Modification of Option 1 by addition of a location edge to facilitate more flexibility in computing over a model and encoding knowledge of tissue expression

In this solution, the location defined by a chosen namespace can be applied in an upfront statement to set the context of the event and subsequent events.  This requires a new scaffolding relationship (e.g.,“Loc”) that specifies a cell-type location, and can act in a similar fashion to a family-type scaffolding relationship.

The benefits are around both knowledge incorporation (capturing tissue expression knowledge from the literature or expression databases) as well as flexibility in scoring where the full mechanism is present and can be used when insufficient knowledge is available around tissue specific versions of a node. As with Option 1, we would still need to ensure multiple conceptual locations were possible in BEL.

 

a(RGD: Pparg) Loc a(RGD: Pparg, loc(namespace: Granulosa Cell))

tscript(a(RGD: Pparg), loc(namespace: Granulosa cells)) decreases a(RGD: Cyp19a1, loc(namespace: Granulosa cells))

a(RGD: Cyp19a1, loc(namespace: Granulosa cells)) increases a(CHEBI: estradiol, loc(namespace: Granulosa cells))

tloc(a(CHEBI: estradiol)), fromLoc(namespace: Granulosa Cell), toLoc(namespace: blood)

a(CHEBI: estradiol, loc(namespace: blood)) increases bp(MESHPP: ”Menstrual Cycle”)

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