Ben Cosgrove
 Ben Cosgrove CV email Epernicus Ph.D. Student Department of Biological Engineering webpage Massachusetts Institute of Technology webpage
"Quantitative Analysis of Cytokine-Induced Hepatocyte Proliferation, Apoptosis, and Toxicity" Many therapeutic approaches, including viral gene therapy agents and small molecule pharmaceutical compounds, are confounded by liver toxicity due to, in part, synergistic relationships with inflammatory stimuli in eliciting hepatocyte toxicity and/or death. My work focuses quantitatively measuring and modeling how hepatocytes regulate, through the activities of intracellular and extracellular signaling networks, cell behavioral responses following cytokine stimulation in the presence of viral gene therapy agents or small molecule drugs in physiologically relevant in vitro cell models. Initially, I examined the role of the inflammatory cytokine tumor necrosis factor-α (TNF), which regulates both hepatocyte proliferation and apoptosis in vivo. I showed that TNF stimulates hepatocyte proliferation and (adenoviral vector infection-sensitized) apoptosis in vitro through a time-varying autocrine cascade involving the growth factor TGF-α and the cytokines IL-1α/β and IL-1ra. I demonstrated that the inducible TGF-α–IL-1α/β–IL-1ra autocrine cascade regulates hepatocyte responses to TNF in a self-antagonizing manner by modulating multiple signaling pathways, including Akt, ERK, JNK, p38, and IKK–NF-κB, downstream of TNFR that both positively and negatively regulate hepatocyte proliferation and apoptosis. Currently, I am developing in vitro models of idiosyncratic drug hepatotoxicity by examining the interactions between multiple pharmaceutical compounds and inflammatory cytokines. In this work, I aim to elucidate how certain idiosyncratic hepatotoxic drugs exhibit synergistic toxicity relationships with inflammatory cytokines by collecting systems-level intracellular signaling data and phenotypic cellular toxicity data. This data set has been used to develop data-driven signaling-outcome models through partial least squares regression (PLSR) approaches to identify and predict key signaling activities that regulate a diverse set of hepatocyte toxicity phenotypes and to inform future therapeutic strategies.
[1] Cosgrove BD, Griffith LG, Lauffenburger DA. Fusing tissue engineering and systems biology toward fulfulling their promise. Cellular and Molecular Bioengineering 1:33-41, 2008. DOI. [2] Cosgrove BD, Cheng C, Pritchard JR, Stolz DB, Lauffenburger DA, Griffith LG. An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-α. Hepatology, 2008. in press.
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