Ben Cosgrove

Biosketch

B.Bm.E., Biomedical Engineering, University of Minnesota, 2003 Ph.D. Candidate, Biological Engineering Division, M.I.T., current

Research Advisors

Prof. Linda G. Griffith, M.I.T. Biological Engineering Division and Department of Mechanical Engineering Prof. Douglas A. Lauffenburger, M.I.T. Biological Engineering Division and Departments of Chemical Engineering and Biology

Primary Collaborators

Prof. Forest M. White, M.I.T. Prof. Donna Beer Stolz, University of Pittsburgh Kathryn Miller, Lauffenburger Lab, M.I.T. Kevin Janes, Lauffenburger Lab, M.I.T. Eileen Dimalanta, Griffith Lab, M.I.T.

Research Focus

“Multivariate Cue-Signal-Response Analysis of Hepatocyte Proliferation and Apoptosis in 2D and 3D Culture Systems”

Cells respond to dynamic soluble and insoluble environmental cues through modified activities of multiple intracellular biochemical signal transduction pathways, often yielding distinct changes in cellular phenotype. Disparate cues, ranging from cell-matrix interactions to cytokine and growth factor binding to interactions with infectious agents, are transduced by a set of shared intracellular signaling and transcriptional networks leading to attenuation and/or integration of multiple cellular stimuli. Therefore, cells can be thought of as biological information processing networks in which multiple inputs are processed by cascades of shared nodes eliciting concerted phenotypic outcomes (e.g. differentiation, proliferation, cell death, survival).

The phenotypic differentiation state of hepatocytes, the liver parenchymal cells, is mediated by soluble signaling factors, cell-cell and cell-matrix interactions. Inspired by the perfused architecture of native liver tissue, a three-dimensional (3D) perfused hepatocyte culture system has been developed [1] and been showed to maintain a hepatic differentiation state more closely resembling that of in vivo hepatocytes than standard two-dimensional (2D) hepatocyte culture systems. Thus, it is hypothesized that 2D and 3D hepatocyte cultures have quantitatively different stimulation of intracellular signaling and transcription pathways as mediated by cell-cell and cell-ECM interactions.

In the aforementioned framework, we aim to apply quantitative analysis of key nodes in multiple intracellular signaling networks and phenotypic cellular outcomes to proliferation and/or apoptosis decision making processes in primary hepatocytes. As model systems, cytokine (TNF-alpha, IL-6)- and growth factor (EGF, HGF, TGF-alpha)-mediated proliferation and replication-deficient adenoviral vector (AdV)-sensitized, TNF-alpha-mediated apoptosis will be examined in 2D and 3D primary hepatocyte cultures. Multivariate, time-resolved signaling activity and phenotypic cellular outcome data will analyzed using principal component analysis (PCA) and discriminant partial least squares regression (DPLSR) to elucidate salient activity variables in hepatocyte biological information processing and formulate predictions of cellular behavior [2].

References

[1] Powers MJ, Janigian DM, Wack KE, Baker CS, Beer Stolz D, Griffith LG. (2002). “Functional behavior of primary rat liver cells in a three-dimensional perfused microarry bioreactor.” Tissue Engineering, 8: 499-513. [2] Janes KA, Kelly JR, Gaudet S, Albeck JG, Sorger PK, and Lauffenburger DA. (2004). “Cue-signal-response analysis of TNF-induced apoptosis by partial least squares regression of dynamic multivariate data.” J. Comput. Biol., 11: 544-561.

Links

Griffith Lab website: http://web.mit.edu/lgglab/
Lauffenburger Lab website: http://web.mit.edu/dallab/