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Making Mechanistic Connections between Cell Signaling Pathways and Pathological EndpointsLilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140, USA, davisma{at}lilly.com Cell signaling is a term used to describe a complex interactive system of signals that act to regulate or mediate a cellular response. Therapies that target cell signaling pathways have the potential to effectively reverse molecular deregulation underlying disease. The inherent complexity of cell signaling presents a major challenge to designing such therapies however, because perturbation of pathways has the potential to produce dramatic adverse effects. Pathologists are in the primary position of detecting adverse responses in drug development and are essential members of teams whose goal is to determine the mechanisms underlying tissue responses. The pathologist therefore will be expected to integrate morphologic interpretation with data obtained from several laboratory-based methods and data derived from novel technologies. Approaches being used include several in silico tools that provide access to public databases and signal pathway visualization that can serve to focus on key mechanistic hypotheses. The main objective of this article is to discuss a basic mechanistic approach and methods that can be used to associate modulation of cell signaling pathways with pathologic endpoints. The approach suggested begins with diagnostic pathology and uses global gene expression analysis in conjunction with transcription factor profiling and confirmatory protein technologies, to elucidate pathways relevant to the biological mechanism. Another important objective is to highlight the use of in silico technologies to prioritize laboratory efforts and focus these efforts on key hypotheses.
Key Words: Cell signaling • kinases • gene regulation • pathology.
Toxicologic Pathology, Vol. 32, No. 1 suppl,
131-135 (2004) |
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