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Vanderbilt University School of
Medicine
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| Office
Address |
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Mailing
Address |
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EBL 406
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400 Eskind Biomedical Library 8340
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| Research
Keywords |
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Mathematical and Systems Biology,Biochemistry,Cell cycle,Gene regulation,Microbiology,Physiology,Protein Structure,Proteomics,Stem cells,Structural Biology,Transcription,Transcription factor,Translation,Yeast |
| Research
Specialty |
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Phenomenology and Quantitation. |
| Research
Description |
In recent years there has been an unprecedented explosion in our knowledge about
the structure and function of genetic regulatory networks. Understanding the function
and dynamics of large biological networks of genes and proteins promises revolutionary changes in how we view and treat
human diseases, and how engineers will design robust and controllable nonlinear circuitry and devices in the future.
The key challenge in many fields of study currently is to understand how the structure of a network
correlates with its dynamical output, and how the behavior of a complex network can be predicted from
a detailed knowledge of a spanning set of component sub-networks.
The barriers obstructing progress are:
A) insufficient data for faithful modeling of the dynamics of large networks,
B) insufficient mathematical understanding of the interplay between the structure of a network and its function and dynamics.
Our current work is an attempt to address this challenge for an ancient, interesting and tractable network of 5 genes that
regulate an aspect of nitrogen utilization in bakers yeast. Our results include a mathematical proof that the cell cycle
forces the concentrations of the products of several key genes to oscillate periodically in phase with the cell cycle.
Currently there does not exist a universal model for the dynamics of gene
regulation that is analogous to the Hodgkin-Huxley model that has been so foundational in the neurosciences.
We view this challenge as a long term goal of our interdisciplinary collaboration that has teamed together
into a functional unit, wet lab biologists, biophysicists, applied mathematicians and a bioinformatician.
Based on detailed quantitative measurements using cutting edge biotechniques, a novel
combinatorial research design that exploits the genetic and biochemical pliability of yeast
as a model organism, and the leverage afforded by Vanderbilt's extensive array of core facilities,
such as the cell imaging shared resource, our team is developing precise models of the dynamical behavior of the
complex nitrogen regulatory circuit. The quantitative models we are developing will allow us to discover mathematical theorems, that relate the structure of the nitrogen circuit to its dynamics and function. In this paper we demonstrate, among other things, our ability to prove theorems for realistic mathematical models of the biological process of gene regulation.
It remains a reductionist dream to build a mathematical model that can respond to stimuli as real cells do.
A brute force effort to describe all the microscopic interactions within a cell with mass action kinetics
will necessarily fail, if for no other reason then a sheer lack of imagination and poetry. We believe that a far more
reasonable, academic and elegant strategy is to search for the very theorems that nature has discovered through eons of adaptation. As medicine begins to target disease on the scale of a single gene product, systems wide nonlinear interactions will require scientists to be able to compute the precise dynamical responses of large network complexes. This will only become feasible through the discovery of the appropriate structure theorems, that is a central goal of our ongoing collaboration.
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| Clinical
Research Description |
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Currently we are working toward developing an artificial immune system for a hospital environment. This involves a dynamical systems model of the interaction between a patient and the health care environment with regard to bacterial load. Given an accurate model, sensors and actuators, measures of control can be studied and implemented. |
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Stowers, CC, Robertson, JB, Ban, H, Tanner, RD, Boczko, EM. Periodic fermentor yield and enhanced product enrichment from autonomous oscillations. Appl Biochem Biotechnol, 156(1-3), 59-75, 2009. Robertson, JB, Stowers, CC, Boczko, E, Johnson, CH. Real-time luminescence monitoring of cell-cycle and respiratory oscillations in yeast. Proc Natl Acad Sci U S A, 105(46), 17988-93, 2008. PMCID:2584751 Boczko, E, Gedeon, T, Mischaikow, K. Dynamics of a simple regulatory switch. J Math Biol, 55(5-6), 679-719, 2007. C. Stowers and E. M. Boczko. Reliable Cell Disruption in Yeast. Yeast, 24, 533-541, 2007. E. M. Boczko, W. Kalies, K. Mischaikow. Polygonal Approximation for Flows
. Toplology and its Applications, 154, 2501-2520, 2007. Hinow, P, Boczko, EM. Molecular seismology: an inverse problem in nanobiology. J Theor Biol, 246(1), 145-58, 2007. P. Hinow and E. M. Boczko. Molecular Siesmology: An inverse problem in nanobiology
. The Journal of Theoretical Biology, 246, 145-158, 2007. Stowers, CC, Boczko, EM. Reliable cell disruption in yeast. Yeast, 24(6), 533-41, 2007. Boczko, EM, Cooper, TG, Gedeon, T, Mischaikow, K, Murdock, DG, Pratap, S, Wells, KS. Structure theorems and the dynamics of nitrogen catabolite repression in yeast. Proc Natl Acad Sci U S A, 102(16), 5647-52, 2005. PMCID:556013 Moore, JH, Boczko, EM, Summar, ML. Connecting the dots between genes, biochemistry, and disease susceptibility:
systems biology modeling in human genetics. Mol Genet Metab, 84(2), 104-11, 2005. E. M. Boczko and T. Young
. Basins of attraction for cascading maps. IJBC, 14, 3557-3566, 2004. Tserng, KY, Ingalls, ST, Boczko, EM, Spiro, TP, Li, X, Majka, S, Gerson, SL, Willson, JK, Hoppel, CL. Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine. J Clin Pharmacol, 43(8), 881-93, 2003. Guo, Z, Brooks, CL, Boczko, EM. Exploring the folding free energy surface of a three-helix bundle protein. Proc Natl Acad Sci U S A, 94(19), 10161-6, 1997. PMCID:23332 Z. Guo, C.L. Brooks III and E.M. Boczko . Exploring the folding free energy surface of a three helix bundle protein. Proc. Natl. Acad. Sci., 94, 10161-10166, 1997. Boczko, EM, Brooks, CL. First-principles calculation of the folding free energy of a three-helix bundle protein. Science, 269(5222), 393-6, 1995. E.M. Boczko and C.L. Brooks III . First principles calculation of the free energy surface for folding of a three helix bundle protein. Science , 269, 393-396, 1995. E.M. Boczko and C.L. Brooks III . Constant temperature free energy surfaces for chemical and physical processes. J.Phys. Chem, 97, 4509-4513, 1993. Herbst, RS, Boczko, EM, Darnell, JE, Babiss, LE. The mouse albumin enhancer contains a negative regulatory element that interacts with a novel DNA-binding protein. Mol Cell Biol, 10(8), 3896-905, 1990. PMCID:360900 Herbst, RS, Pelletier, M, Boczko, EM, Babiss, LE. The state of cellular differentiation determines the activity of the adenovirus E1A enhancer element: evidence for negative regulation of enhancer function. J Virol, 64(1), 161-72, 1990. PMCID:249075 R.S. Herbst, E.M. Boczko, J.E. Darnell Jr. and L.E. Babiss . The mouse albumin enhancer contains a negative regulatory element that interacts with a novel DNA-binding protein. Mol.Cell.Biol., 10, 3896-3905, 1990. R.S. Herbst, M. Pelletier, E.M. Boczko, and L.E. Babiss . The state of cellular differentiation determines the activity of the adenovirus E1A enhancer element: Evidence for negative regulation of enhancer function. J.Virology , 64, 161-172, 1990. |
| Postdoctoral
Position Available |
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Yes |
| Postdoctoral
Position Details |
Postdoctoral position in Systems Biology:
Some of our recent work involves understanding the nature of microbial communication. We have shown that feedback within the cell cycle can causes a cell population to organize into clusters in time and in space along the cell cycle . We are studying this phenomena and how to exploit it. We are interested in phenomenology and quantitation. Postdoctoral candidates looking for an interdisciplinary project are invited to apply.
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