The Systems Biology of Drug Action

Authors

Ravi Iyengar, PhD, Mount Sinai School of Medicine, New YorkFollow

Document Type

Presentation

Publication Date

4-17-2013

Comments

The annual William Potter lecture was created by the late William Potter Wear, a Jefferson Life Trustee, to honor his grandfather and former President of the Jefferson Medical College and Hospital Board of Trustees, the Honorable William Potter, LLD.

Abstract

The Iyengar laboratory is interested in understanding how signals are routed and processed through cellular signaling networks including mechanisms of information sorting and integration.

We are interested in understanding dynamics of network topology. For this we focus on identifying regulatory motifs such as feedback and feedforward loops and determining their information processing capability. We have constructed and analyzed dynamic maps of these motifs to understand how cellular signaling networks engage the various cellular machinery to produce physiological responses to extra-cellular signals. To study complex cell signaling networks we utilize a combination of experimental and theoretical approaches. Multidimensional experimental approaches currently being used in the laboratory include reverse-phase phosphoproteomic arrays, transcription factor arrays, ChIP-Seq and mRNA profiling by sequencing. These experimental approaches are being integrated with theoretical analysis using both graph theory approaches and differential equation based modeling to understand network regulation of cell proliferation and activity induced synaptic plasticity.

We are interested in understanding how spatial organization within cells and tissues contributes to dynamic stability. We are studying the role of cell shape in regulating information processing within signaling networks. For these studies at the experimental level we are using approaches to observe and quantify biochemical signaling reactions in live cells. We are also using patterned surfaces at the nano and microscale as to obtain cells of specific shapes that can be imaged. To decipher the information content in cell shape we are analyzing signaling networks using partial differential equations. We are developing spatially realistic models of signaling networks to understand the origins and dynamics of microdomains of signaling components. We are also interested in understanding the dynamics underlying tissue integrity. We are developing multi-scale models as well as experimentally engineered systems to determine if a dynamic loop that integrates signaling networks in multiple cell types forms the basis for tissue integrity.

We are developing systems level approaches to understanding drug action at a genome-wide level. We are constructing large scale networks to capture all of the known protein-protein interactions in the human genome to computationally identify selective regions (disease neighborhood) within the interaction space associated with specific diseases. We are analyzing the relationship between drug targets and other cellular components to understand the relationship between disease neighborhood and targets of drugs used to treat the disease. From such analyses we are attempting to predict adverse events and explain adverse events reports in the FDA–AERS database.

• Systems biology and systems pharmacology
• Computational cell biology
• Cellular signaling networks
• Spatial modeling of cell signaling
• G-protein mediated intracellular signaling in neurons
• Spatiotemporal organization of cellular networks

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