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Gerard Ostheimer

Current position: AAAS Science & Technology Policy Fellow, USDA

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Education

PhD University of Oregon, 2003
MS Montana State University, 1992
AB Dartmouth College, 1990

Research

The DNA damage signaling network can be thought of as a computational device in which the input is the type and extent of the DNA damage and the output is cell cycle arrest and repair, permanent cell cycle arrest or cell death. To understand how these cell fates are determined we have generated a quantitative, network level understanding of how this cellular decision process works through the synergistic application of experimental and computational methods. Doxorubicin induced DNA damage in combination with TNFα, which is a cytokine commonly found in tumor microenvironments, was used to drive populations of cells to different levels of senescence and apoptosis. We captured the cellular information processing by monitoring the DNA damage response, cell cycle machinery, apoptosis machinery and the stress/mitogen activated protein kinases. We intentionally used single cell methods such as flow cytometry and fixed cell immunofluorescence in order to be able to monitor the evolution of cell populations. Using flow cytometry quantified proliferation, cell cycle arrest kinetics and apoptosis levels. Concomitantly, we have used high-content, fixed cell immuno-fluorescence of protein level, protein localization and phosphorylation state to observe 30 signaling proteins within the cell. Partial Least Squares Regression of the signaling data against the response data identifies the anticipated components of the DNA damage response signaling pathways (e.g. gH2AX, p53), cell cycle machinery (e.g. Cyclin B, p21), apoptosis machinery (e.g. Bcl-XL) that regulate the cellular decision to apoptose or senesce. The regression analysis also identifies roles for the stress/mitogen activated protein kinase signaling pathways in modulating the cellular response to DNA damage. In particular, we have found that the activities of Erk, p38, Jnk and Akt control whether a cell senesces or apoptosis. Armed with this network understanding of how intra-cellular signaling defines phenotypic outcome we are capable of engineering the fate of heterogeneous cell populations. Such controlled modulation of cell fate could prove invaluable in a clinical or engineering situation.

Publications

Toettcher, J.E., Loewer, A., Ostheimer, G.J., Yaffe, M.B., Tidor, B. and Lahav, G. (2009) Distinct mechanisms act in concert to mediate cell cycle arrest. Proc. Natl. Acad. Sci. USA 106, 785-90.

Linding, R., Jensen, L.J., Ostheimer, G.J., van Vugt, M.A., Jørgensen, C., Miron, I.M., Diella, F., Colwill, K., Taylor, L., Elder, K., Metalnikov, P., Nguyen, V., Pasculescu, A., Jin, J., Park, J.G., Samson, L.D., Woodgett, J.R., Russell, R.B., Bork, P., Yaffe, M.B., and Pawson, T. (2007) Systematic discovery of in vivo phosphorylation networks. Cell 129, 1415-26.

Ostheimer, G.J.,Rojas, M. Hadjivassiliou, H., and Barkan, A. (2006) Formation of the CRS2-CAF2 group II intron splicing complex is mediated by a 22-amino acid motif in the COOH-terminal region of CAF2. J. Biol. Chem. 281, 4732-4738.

Ostheimer, G.J., Hadjivassiliou, H., Kloer, D.P., Carrier-Williams, R., Barkan, A., and Matthews, B.W. (2005) Structural analysis of the group II intron splicing factor CRS2 yields insights into its protein and RNA binding surfaces. J. Mol. Biol. 354, 51-68.

Ostheimer, G.J., Carrier-Williams, R., Belcher, S., Osborne, E., Gierke, J., and Barkan, A. (2003) Group II intron splicing factors derived by duplication and diversification of an ancient RNA binding domain. EMBO J. 22, 3919-3929.

Ostheimer, G.J., Barkan, A., and Matthews, B.W. (2002) Crystal structure of E. coli YhbY: A representative of a novel class of RNA binding proteins. Structure 10, 1593-1601.

Wray, J.W., Baase, W.A., Ostheimer, G.J., Zhang, X.J., and Matthews, B.W. (2000) Use of a non-rigid region in T4 lysozyme to design an adaptable metal-binding site. Protein Eng. 13, 313-321.

Tilly, K., Hauser, R., Campbell, J., and Ostheimer, G.J. (1993) Isolation of dnaJ, dnaK, and grpE homologues from Borrelia burgdorferi and complementation of Eschericia coli mutants. Mol. Microbiol. 7, 359-369.

Ostheimer, G.J., Starkey, J.R., Lambert, C.G., Helgerson, S.L., and Dratz, E.A. (1992) NMR constrained solution structures for laminin peptide 11: Analogs define structural requirements for inhibition of tumor cell invasion of basement membrane matrix. J. Biol. Chem. 267, 120-128.

Collaborators

Case Western University: Evren Gurkan-Cuvasuglu, Ken Loparo
Harvard: Bjorn Millard, Mario Niepel, Julio Saez-Rodriguez
Moffit Cancer Center: Sandy Alexander
Vanderbilt: Vito Quaranta, Alissa Weaver
Virginia Tech: Tongli Zhang, John Tyson

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This page last modified on July 3rd, 2012