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"Multivariate Cue-Signal-Response Analysis of TNFα-Induced Hepatocyte Proliferation and Apoptosis"
"Multivariate Cue-Signal-Response Analysis of TNFα-Induced Hepatocyte Proliferation and Apoptosis"


In the liver, the pleoitropic cytokine tumor necrosis factor-α (TNFα) induces hepatocytes to undergo multiple cellular decision processes including proliferation, survival, and apoptosis (programmed cell death) that are highly sensitive to a variety of physiologically relevant co-stimuli such as mitogenic growth factors and viral infection. During liver regeneration, TNFα and other mitogenic stimuli (HGF, EGF, TGFα) are secreted by liver non-parenchymal cells and induce proliferation of differentiated hepatocytes.  Upon viral infection by pathogenic species or common gene therapy vectors such as adenovirus, liver non-parenchymal cells secrete TNFα and other pro-inflammatory cytokine that stimulate virus-infected hepatocytes to undergo apoptosis.  Our understanding of the mechanisms that mediate TNFα-induced hepatocyte outcomes is limited by (i) the extent of extracellular cross-talk between hepatocytes and liver non-parenchymal cells through paracrine and autocrine mediators, (ii) the extent of intracellular cross-talk between signaling pathways downstream of TNFα and other physiologically relevant co-stimuli in hepatocytes, and (iii) the effects of hepatocyte de-differentiation in standard in vitro culture systems. 
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 propose to characterize TNFα-mediated hepatocyte responses through a multivariate cue-signal-response paradigm by which multiple intracellular signaling activities, extracellular autocrine cascades, and phenotypic cellular outcomes are rigorously quantified upon co-stimulation with either growth factors or a replication-deficient adenovirus using both standard two-dimensional and novel three-dimensional rat hepatocyte culture systems.  Multivariate signaling and cellular outcome data will be subsequently analyzed using data-driven modeling and analysis methods such as principal component analysis and partial least squares regression to develop and validate predictive models of hepatocyte decision processes related to the phenomena of liver regeneration and viral infection responses.  
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.




Revision as of 05:53, 20 July 2006

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Ben Cosgrove CV email

Ph.D. Student

Biological Engineering Division webpage

Massachusetts Institute of Technology webpage


Research Advisors:


Research Summary:

"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.


Member of:


Funding:

  • Whitaker Foundation Graduate Research Fellowship webpage
  • MIT-Pfizer Hepatoxicity Signaling Collaboration webpage internal wiki
  • MIT Center for Cell Decision Processes webpage
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