Systems Biology of Cell Signaling and Drug Responses through Modeling and Microscopy
Tuesday, October 20, 2015
3:00 p.m.-4:00 p.m.
FDA White Oak Location, Bldg. #2 room 2031
301 405 0285
Dr. Myong-Hee "Mia" Sung uses diverse systems biology approaches to study cell signaling dynamics and transcription control. Using mathematical modeling and optical imaging techniques, she revealed sustained asynchronous oscillations of NF-kappaB activity in individual cells exposed to a pro-inflammatory cytokine TNF-alpha. Dr. Sung has developed novel computational methodologies to analyze and extract biologically meaningful information from massive genomics data such as DNase-seq, ChIP-seq, and 4C. With her expertise in chromatin biology and computational genomics, she has also been overseeing a Center for Cancer Research initiative on cancer chromatin profiling. Dr. Sung is starting a new position at the National Institute on Aging, NIH Baltimore, in the fall of 2015 as an Earl Stadtman Investigator and Section Chief of the newly established Transcription Systems Dynamics and Biology Unit. Her laboratory will use single cell imaging, mathematical methods, and genomics tools to investigate biological information encoded in the dynamics of signaling and transcription networks.
NF-κB, a key transcriptional regulator of inflammation and cell survival, operates within a complex regulatory network. Theoretical considerations lead to the possibility of stimulus-induced oscillations in the network with multiple ‘waves’ of NF-κB accumulation in the nucleus. Numerous other transcription factors possess similar potential for oscillatory activity.
Our study of the real time dynamics of NF-κB in living cells using GFP knock-in mouse fibroblasts is an experimental validation of such oscillations in a physiological system. The nuclear level of NF-κB oscillates asynchronously up to several cycles in response to TNF-α. Mathematical modeling suggests that negative feedback loops do not simply terminate signaling, but rather promote NF-κB oscillations possibly for a functional advantage. Single fibroblasts respond to a range of TNF-α concentrations in a digital all-or-none fashion. More recently, we have uncovered a distinct principle of NF-κB signaling by examining macrophages responding to bacterial stimuli. In this immune cell type, the NF-κB network is re-wired by a novel positive feedback mechanism for analog signal processing and phenotype-switching to a fully active anti-bacterial response.
Dynamics of TF signaling may influence the ultimate outcome of cell responses to environmental stimuli. Perturbed dynamics of the target molecular networks during targeted therapy may produce non-intuitive effects. The proposed systems cell biology approach should be utilized to address these issues in basic and translational biology. Such knowledge is required for optimal intervention of complex molecular networks in targeted therapy.
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