Immunology Team Contributions to the LSB

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Over the past several years, we have contributed to this project in several ways. First, we conducted a detailed analysis of multi-ligand stimulation of macrophages by TLR ligands that set the stage for creation of a detailed biochemical model of these processes using the Simmune modeling environment, research that is now being extended by former LBS fellow Dr. Rachel Gottschalk in collaboration with LISB PI Dr. Martin Meier-Schellersheim. We also previously developed a model system for employing the tools of systems biology to investigate the unexplored roles of many NLRs. In the course of such study, Dr. Subramanian (now leading her own laboratory at the Institute for Systems Biology) observed profound effects of very small changes in intracellular protein concentration on signaling through the NOD1 pathway. Under normal conditions, several miRNAs contribute to maintaining expression of NOD1 below the level leading to ligand-independent gene activation. Alteration in expression of these miRNAs is linked to an increases severity of gastric cancer, which was previously linked to NOD1. These data may be of importance in understanding how small eQTLs linked to inflammatory and autoimmune diseases operate to cause pathology. Based on these findings, we are exploring in various experimental systems whether small (1-2 fold changes in gene expression, as seen with many eQTLs), can lead to disease by imbalancing activation and negative regulatory pathways. We suspect this type of dysregulation might contribute to various autoimmune states (see AI000758-26). Other work in the LBS reveals that clonal T cell populations vary in both protein expression and in associated functional capacity and that these states vary over time in the absence of cell division. This suggestion of time fluctuations in cell state have important implications for better understanding when individual immune cells respond to perturbations, when they might exceed regulatory control thresholds, and how small eQTL-level differences in average gene expression might contribute to disease propensity. Finally, we have developed the FILMSTAR system for real-time imaging of signaling events in a model human T cell system. The reagents developed for FILSTAR are being used in other laboratories to study intracellular signaling and by members of the LISB in diverse projects.