Taking a Systems Approach to the Identification of Novel Therapeutic Targets and Biomarkers

David      A. Dunn; Donald      Apanovitch; Max      Follettie; Tao      He; Terence      Ryan

Abstract

Systems biology focuses on the roles of cellular pathways and networks rather than single biomolecules to describe biological function. A systems view of biology requires technology that can generate and quantitatively analyze, large multi-dimensional data sets from many different sources. New technology has made this approach to drug discovery increasingly feasible. Detailed changes in cellular phenotype can be quantitatively measured using high content phenotypic screens. Changes in a cells entire transcriptome or proteome can be profiled in detail. Libraries of small molecules, peptides or poly-nucleotides such as siRNA can be screened to identify perturbagens that modulate transcriptomic, proteomic and cellular phenotypic signatures. These molecular agents can be used to deconvolute pathways and networks. The power of these technologies lies in their ability to generate complex biological data at massive scales. Integration and analysis of this multi-parametric data is vital to systems biology research. Patterns and relationships within these data sets can be revealed using factor and principal component analysis. These patterns can point to pathways that are relevant to specific biological processes making the ultimate goal of understanding the biology of a cell at the systems level possible.

Keywords: Chemical biology, high content screening, multivariate analysis, ontological classification, predictive modeling, proteomics, transcriptomics, G-protein coupled receptors, signaling networks, chemokine receptors, Her2 receptor, cellular proliferation, therapeutic agents, Small molecule perturbagens, wide-field imagers, Nipkow disk, confocal based laser scanning cytometers, automated microscopy, image analysis, polymer-cell interactions, robotic dispensing systems, conjugating organic fluorescent dyes, green fluorescent protein, Saccharomyces cerevisiae, Danio rerio, Cae-norhabditis elegans, RNA interference technology, mTOR pathway, FOXO, PI3K/AKT signaling, Ca2+/calmodulin signaling, Principal component analysis, Open Microscopy Environment, Cell Profiler Analyst platforms, com-parative genome hybridization, Taqman low-density arrays, Gene Set Enrichment Analysis, isotope-coded affinity tagging, immobilized metal-ion affinity chromatography, multiple ion reaction monitoring, elect-ro capture dissociation, electron transfer