Lauffenburger:Cell Signaling and Regulatory Networks

Lauffenburger Lab

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Cell Signaling and Regulatory Networks In this area we are attempting to understand, in terms of quantitative systems dynamics, regulation and dysregulation of cell phenotypic behavioral responses (e.g., death, proliferation, differentiation, migration) as governed by signaling networks activated by growth factors, cytokines, and extracellular matrix. We have a major focus on the EGF receptor family, which is strongly implicated in cancer progression, and on the TNF receptor family, which is involved in cell death/survival decisions in response to tissue. Our goal is to develop predictive computational models for cell phenotypic decisions in terms of underlying signaling network properties, with application to drug discovery and development. Bree Aldridge (BE doctoral), in collaboration with Prof. Peter Sorger (Biol/BE, MIT), and Drs. David DeGraaf & Jack Beusmans (Astra-Zeneca) Computational modeling and analysis of the apoptosis/survival signaling network. Current work concentrates on developing an physio-chemical insulin signaling model, model merging (of the insulin, EGF, and TNF pathways), and adapting analysis methods to understand large biochemical signaling networks John Burke BE postdoctoral in collaboration with Peter Sorger (MIT Biology), Jack Beusmans (AstraZeneca), and Birgit Schoeberl (Merrimack Pharmaceutical). Mathematical modeling, analysis, and simulation of cellular signaling pathways and protein synthesis. Working closely with experimentalists and computational biologists I derive, from first principles, and study math models describing biological systems. I use dynamical systems, multiple time-scale, singular and random perturbation techniques to analyze and mathematically control these systems. I then use simulations to verify analysis. Systems of interest include: generalized MAPK cascades; specific Erk and AKT cascades with cross talk; ErbB Receptor activation, trafficking, synthesis and degradation; Apoptosis/TNF signaling; and mutant ErbB signaling. Ben Cosgrove (BE Doctoral), in collaboration with Prof. Linda Griffith (BE/ME, MIT) Quantitative analysis of cell signaling activities and phenotypic cellular outcomes (proliferation, apoptosis, survival) in primary hepatocytes induced by the cytokine TNFα and physiologically relevant pro-growth (e.g. EGF, HGF) or pro-apoptotic (e.g. viral infection) co-stimuli administered in standard two-dimensional and novel three-dimensional culture systems. Multivariate signaling activity and proliferation/apoptosis outcome data are analyzed using data-driven methods to explore intracellular and extracellular cross-talk and feedback mechanisms regulating hepatocyte decision-making processes. Sampsa Hautaniemi (BE postdoctoral) Systems biology and data mining approaches to explore multivariate biomedical phenomena. Main research interests include modeling complex molecular level interactions using supervised and unsupervised learning methods, data analysis and statistical experimental design. Current work concentrates on the analysis of signal transduction pathways. Melissa Kemp (BE postdoctoral), in collaboration with Lucia Wille, John Burke, Christina Lewis Investigation of the signaling dynamics and cytokine responses resulting from stimulation of the T cell receptor via ligands of varying avidity. Using a systems approach, we have generated a large dataset characterizing the multivariate relationships between ligand avidity, signaling dynamics and IL-2 production in a murine T cell hybridoma line. Partial least squares regression analysis leads to a predictive model of IL-2 production in our system. Neil Kumar (ChE doctoral), in collaboration with Drs. David DeGraaf & Jack Beusmans (Astra-Zeneca) Quantitative analysis, both experimental and computational, of the effects of HER2 overexpression on the cell signaling network and cell behavior. High throughput experimental methodologies employed and optimized for exploration of cell signaling dynamics and cell behavior. Multiple computational approaches at different levels of abstraction employed for modeling studies and data analysis. Christina Lewis (Lab Manager) Research focuses on how various molecular parameters affect the efficacy of therapeutics targeted at the ErbB pathway and quantitative comparisons of the efficacy for different therapeutic modes of action. The process involves measuring ERK activity levels on cells treated with such therapeutics and comparing the results to predictions from model simulations. Ericka Noonan (BE doctoral), in collaboration with Prof. Leona Samson (BE, MIT) Analysis of the signaling events downstream of DNA damage, specifically damage produced by alkylating agents, and how these signals control the cellular response of death/survival. Megan Palmer (BE doctoral) Quantitative experimental and computation analysis of the mechanisms of signaling network cross-talk downstream of the T cell receptor and interleukin (IL)-2 family cytokines (IL-2, IL-7 and IL-15) in naïve CD8 T cells. Robin Prince (ME masters), in collaboration with Prof. Roger Kamm (ME/BE, MIT) and Prof. Richard Lee (Brigham & Women's Hospital, Harvard) Experimental and computational modeling studies of HB-EGF ligand/receptor signaling in cardiac myocytes as related to cardiac hypertrophy and the expression of the gap junctional protein, Connexin43. Karen Sachs (Toxicology doctoral), in collaboration with Prof. David Gifford (EECS, MIT) and Prof. Tommi Jaakkola (EECS, MIT) Analysis of signaling networks using Bayesian network modeling; application to single cell multidimensional flow cytometry measurements of signaling proteins in primary human T cells (in collaboration with Prof. Garry Nolan, Stanford). Current focus is on analysis of differential signaling in disparate cell states. Lucia Wille (Biology doctoral) Understanding the molecular mechanisms of T cell receptor ligand affinity discrimination using altered peptide ligands to correlate T cell fates including cytokine production and activation induced cell death with quantitative measurements of signaling cascade activation. Ale Wolf-Yadlin (BE doctoral) in collaboration with Forest White (BE, MIT) Analysis of signaling networks using mass spectrometry based phosphotyrosine proteomics. The first goal is to be able to quantify the variations of tyrosine phosphorylation over time at the level of whole pathways given a cue. The second goal is to be able to determine the effect of different receptor tyrosine kinases and /or different cytokines in the activation and signal transduction of a given pathway.