Ben Cosgrove
 Ph.D. Student Biological Engineering Division webpage Massachusetts Institute of Technology webpage
"Multivariate Cue-Signal-Response Analysis of TNFα-Induced Hepatocyte Proliferation and Apoptosis" Hepatocytes respond to a diverse set of environmental cues, ranging from cell-matrix interactions to cytokine and growth factor stimuli to interactions with infectious agents, through the modified activities of multiple intracellular and extracellular signaling pathways that control cellular outcomes including proliferation, survival, apoptosis, and differentiated function. For example, the inflammatory cytokine TNFα induces disparate hepatocyte cell decision processes including proliferation and apoptosis that are highly sensitive to physiologically-relevant co-stimuli such as mitogenic growth factors and viral infection. We aim to develop a systems-level approach to elucidate how hepatocytes transduce multiple pro-growth and pro-death cues into distinct cellular fates. This approach will leverage multivariate cell signaling activity data, comprised from distributed sampling of intracellular kinase networks and extracellular autocrine cascades, using statistical approaches such as principal component analysis and partial least squares regression to develop predictive models of the relationship between signaling network activities and phenotypic outcomes in hepatocytes. As pro-growth and pro-death model systems, TNFα- and growth factor-induced proliferation and adenoviral vector-sensitized, TNFα-induced apoptosis will be characterized using in vitro primary hepatocyte cultures. Data-driven models of hepatocyte decision processes could be utilized to design and validate therapeutic strategies related to liver regeneration, liver cancer, viral gene therapy, and drug toxicity.
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