Automated assembly of cell-type-specific mechanisms for the regulation of pain and inflammation with INDRA

INDRA integrates multiple text-mining systems and pathway databases to automatically extract mechanistic knowledge from the biomedical literature and through a process of knowledge assembly, build executable models and causal networks. Based on profiling and perturbational data, these models can be contextualized to be cell-type specific and used to explain experimental observations or to make predictions.

In the context of the DARPA Panacea program, the INDRA team at the Laboratory of Systems Pharmacology, Harvard Medical School is working on understanding the regulation of pain and inflammation with the goal of finding new therapeutics using INDRA.

• Ion-channel mechanism knowledge base
• Ion-channel inhibitor search
• A self-updating model of pain mechanisms
• Neuro-immune interactome
• General applications
• Funding

Ion-channel mechanism knowledge base

We used INDRA to assemble all mechanisms that 65 ion-channels that are particularly important for nociception are involved in.

Each ion-channel’s interactions can be browsed as networks at NDEx.

And the literature evidence can be inspected on the pages linked to below. These pages alsow support expert curation of statements which are fed back to INDRA to improve the models (see curation tutorial here.

CACNA1A CACNA1B CACNA1C CACNA1D CACNA1E CACNA1F CACNA1G CACNA1H CACNA1I CACNA1S HCN1 HCN4 KCNA1 KCNA10 KCNA2 KCNA3 KCNA4 KCNA5 KCNA6 KCNA7 KCNB1 KCNB2 KCNC1 KCNC2 KCNC3 KCNC4 KCND1 KCND2 KCND3 KCNF1 KCNG1 KCNG2 KCNG3 KCNG4 KCNH1 KCNH2 KCNH3 KCNH4 KCNH5 KCNH6 KCNH7 KCNH8 KCNK18 KCNK2 KCNMA1 KCNN1 KCNQ1 KCNQ2 KCNQ3 KCNQ4 KCNQ5 KCNS1 KCNS2 KCNS3 KCNV1 KCNV2 SCN10A SCN11A SCN1A SCN2A SCN3A SCN4A SCN5A SCN8A SCN9A

Ion-channel inhibitor search

The ion-channel inhibitor search is an application that allows selecting some ion-channels as “desirable” drug targets and others as “undesirable” drug targets. The application then searches all INDRA Statements in the ion-channel knowledge base, combined with the Small Molecule Suite / Target Affintiy Spectrum data to find regulators (drugs or other entities that may be relevant) with the desired properties.

The ion-channel inhibitor search is available here.

A self-updating model of pain mechanisms

EMMAA (Ecosystem of Machine-maintained Models with Automated Analysis) makes available a set of computational models that are kept up-to-date using automated machine reading, knowledge-assembly, and model generation, integrating new discoveries immediately as they become available.

The EMMAA model representing pain mechanisms can be found here.

Neuro-immune interactome

Using transcriptional data collected in the Woolf lab of immune cells and neurons following injury, we are building cell-type specific models of how immune cells and pain sensing neurons interact.

The latest set of cell-type specific interactions can be browsed on these pages: DCs Monocytes Dermal macrophages Resident macrophages M2a macrophages M2b macrophages

General INDRA applications

There are several applications built on top of INDRA that that are generally applicable to biomedical research and can therefore also be used to study pain mechanisms.

• INDRA database: The INDRA database website provides a search interface to find INDRA Statements assembled from the biomedical literature, browse their supporting evidence, and curate any errors. Az example search relevant to Panacea is Object: SCN10A to find entities that regulate the Nav 1.8 ion channel.
• INDRA network search: The INDRA network search allows finding causal paths, shared regulators, and common targets between two entities. An example search relevant to Panacea is Subject: bradykinin, Object: PKC (see here).
• Dialogue.bio: The dialogue.bio website allows launching dedicated human-machine dialogue sessions where you can upload your data (e.g., DE gene lists or gene expression profiles), discuss relevant mechanisms, and build model hypotheses using simple English dialogue. For instance, you could try the following series of questions: “what is Nav1.8?”, “what does it regulate?”, “which of those are transcription factors?”.

Funding

This project is funded under the DARPA Panacea program (HR00111920022).