Abstract

Exploring Immune Signaling Systems with High Throughput, High Content Screening.

Iain Fraser, Head, National Institutes of Health

Modern technology now allows the analysis of immune responses and host-pathogen interactions at a global level, across scales ranging from intracellular signaling networks to individual cell behavior to the functioning of a tissue, an organ, and the whole organism. The challenge is not only to collect the large amounts of data such methods permit, but also to organize the information in a manner that enhances our understanding of how the immune system operates or how pathogens affect their hosts. Our laboratory is part of a systems biology program at the NIH whose goal is to develop detailed quantitative models that can be used to predict the behavior of a complex biological system, whose properties help explain the mechanistic basis for physiological and pathological responses to infection or vaccination and can be used to design new therapies or vaccines. We use high-throughput genome-scale technologies (such as siRNA screening and profiling of RNA expression and protein modification) to broadly characterize the cellular response to pathogenic stimuli. I will describe data from ongoing projects in our lab including: €Genome-wide RNAi screens to characterize signaling network topology in hematopoietic cells and to identify the "parts list" of cellular components involved in immune cell responses. €Development of multicolor cell-based fluorescence assays for screening applications and parameterization of computational models. €Use of the above methods to characterize the response of immune cells to defined stimuli, such as single and combined pathogenic ligands, and intact pathogens, such as bacteria and viruses.