Ben Cosgrove

Lauffenburger Lab

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Ben Cosgrove CV email Epernicus Ph.D. Student Biological Engineering Division webpage Massachusetts Institute of Technology webpage Research Advisors: Linda Griffith webpage Doug Lauffenburger webpage lab wiki Research Summary: "Quantitative Analysis of Cytokine-Induced Hepatocyte Proliferation, Apoptosis, and Toxicity" Many therapeutic agents, including viral gene therapy vectors and small molecule pharmaceutical compounds, are confounded by liver toxicity due to, in part, relationships with inflammatory stimuli in eliciting hepatocyte toxicity and/or death. Our work focuses on developing physiologically relevant in vitro approaches to quantitatively assess how hepatocytes regulate, through the activities of intracellular and extracellular signaling networks, cell fate decisions related to proliferation, survival, apoptosis, and differentiated function following cytokine stimulation in the presence of viral gene therapy agents or small molecule drugs. Initially, we examined the role of a specific inflammatory cytokine, tumor necrosis factor alpha (TNF), which regulates both hepatocyte proliferation and apoptosis in vivo. We have shown that TNF stimulates hepatocyte proliferation and (adenoviral vector-sensitized) apoptosis in vitro through an inducible and time-varying autocrine cascade containing the growth factor TGF-α and the cytokines IL-1α/β and IL-1ra. This TGF-α–IL-1α/β–IL-1ra autocrine cascade regulates TNF-induced hepatocyte proliferation and apoptosis responses in a self-antagonizing manner by contributing to multiple signaling pathways, including Akt, ERK, JNK, p38, and IKK–NF-κB, downstream of TNFR. Currently, we are developing in vitro models of idiosyncratic drug hepatotoxicity by examining the interactions between multiple pharmaceutical compounds and inflammatory cytokines. In this work, we 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. Publications: 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. submitted. Cosgrove BD, Griffith LG, Lauffenburger DA. Fusing tissue engineering and systems biology toward fulfulling their promise. Cellular and Molecular Bioengineering, 2008. in press. Member of: MIT Biotechnology Process Engineering center webpage MIT Center for Cell Decision Processes webpage internal wiki Funding: Whitaker Foundation Graduate Research Fellowship webpage MIT-Pfizer Hepatoxicity Signaling Collaboration webpage internal wiki