TITLE: “Constructing a Functional Interactome from Published Work to Identify Underrepresented and Integrative Effects of Neuroinflammatory Cytokines on Neural Excitability.”
ABSTRACT: Maintaining normal excitability is a key function of our nervous system which is subject to ongoing perturbations such as aging and chronic neurodegeneration. Neuroinflammatory responses which are widely associated with injury and disease are often disregarded as ongoing modulators of brain excitability. Indeed, neuroinflammatory cytokines such as TNF-α released by resident glial cells in the nervous system can modify ionic conductivity in neurons at nano-molar concentrations at acute and chronic timescales and in turn can mediate emergence of neural dysfunctions observed during disease development. This suggests that understanding how and when cytokines act on neurons could represent targets for therapeutic modulation. Therefore, we set out to examine in existing literature how strong are the evidence for neuroinflammatory modulation of neural excitability. Surprisingly, neither the database search using popular bioinformatics tools such as the STRING, nor the top hits on Pubmed search using keywords such as “cytokine” AND “ion channels” revealed strong evidence for molecular interactions between inflammatory cytokines in the brain and voltage-gated ion channel proteins responsible for neural signaling. However, a more detailed examination of the literature uncovered a few yet convincing mechanistic studies demonstrating that cytokines can induce changes in ionic conductivity, ion channel protein expression as well as action potential frequencies. Driven by these findings, we set out to develop a novel functional interaction score (FIS) to quantitate the strength of evidence for cytokine actions on neural excitability. We then used such scores to generate a protein-protein interactome to enable further application of graph theory-based approaches to analyze the functional links between neuroinflammation and neural excitability. Our analysis and novel scoring also revealed 1-to-N associations between cytokines and ion channel proteins. In my talk, I will discuss this journey and also share our ongoing innovative approach using the cytokine-ion channel associations in dynamic neuron models as predictive tools to test integrative actions of cytokines on neuronal excitability.
