Computational model of brain endothelial cell signaling pathways predicts therapeutic targets for cerebral pathologies

Abstract

Brain endothelial cells serve many critical homeostatic functions. In addition to sensing and regulating blood flow, they maintain blood-brain barrier function, including precise control of nutrient exchange and efflux of xenobiotics. Many signaling pathways in brain endothelial cells have been implicated in both health and disease; however, our understanding of how these signaling pathways functionally integrate is limited. A model capable of integrating these signaling pathways could both advance our understanding of brain endothelial cell signaling networks and potentially identify promising molecular targets for endothelial cell-based drug or gene therapies. To this end, we developed a large-scale computational model, wherein brain endothelial cell signaling pathways were reconstructed from the literature and converted into a network of logic-based differential equations. The model integrates 63 nodes (including proteins, mRNA, small molecules, and cell phenotypes) and 82 reactions connecting these nodes. Specifically, our model combines signaling pathways relating to VEGF-A, BDNF, NGF, and Wnt signaling, in addition to incorporating pathways relating to focused ultrasound as a therapeutic delivery tool. To validate the model, independently established relationships between selected inputs and outputs were simulated, with the model yielding correct predictions 73% of the time. We identified influential and sensitive nodes under different physiological or pathological contexts, including altered brain endothelial cell conditions during glioma, Alzheimer's disease, and ischemic stroke. Nodes with the greatest influence over combinations of desired model outputs were identified as potential druggable targets for these disease conditions. For example, the model predicts therapeutic benefits from inhibiting AKT, Hif-1α, or cathepsin D in the context of glioma - each of which are currently being studied in clinical or pre-clinical trials. Notably, the model also permits testing multiple combinations of node alterations for their effects on the network and the desired outputs (such as inhibiting AKT and overexpressing the P75 neurotrophin receptor simultaneously in the context of glioma), allowing for the prediction of optimal combination therapies. In all, our approach integrates results from over 100 past studies into a coherent and powerful model, capable of both revealing network interactions unapparent from studying any one pathway in isolation and predicting therapeutic targets for treating devastating brain pathologies.

Keywords: Cerebrovasculature; Computational model; Endothelium; Focused ultrasound; Molecular signaling.