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P. Thomas (Mathematics, Biology & Cognitive Science) and H. Baskaran
(Chemical Engineering & Biomedical Engineering) have formed a new
collaboration to investigate quantitatively the dynamics of
information processing and decision making in biochemical signaling
networks controlling eukaryotic chemotaxis. The proposed work will
combine experimental, computational and theoretical approaches to
studying the chemotactic response to precise spatially and temporally
controlled chemical stimuli. Specified spatiotemporal patterns of
chemical signals will be prepared by a microfabricated fluidic control
device. Single cell responses will be measured through cell motility
assays and fluorescence measurements of intracellular signaling
protein spatial distributions. In close collaboration with
experimental efforts, novel mathematical and computational techniques
will be applied to modeling the biochemical network controlling
directed cell movement, including Monte Carlo simulation, information
theoretic and finite element analysis of reaction-diffusion equations.
There are opportunities for interdisciplinary teams of undergraduate
mathematics, biology and statistics students to participate in all
aspects of this project.
Directed cell movement, or chemotaxis, is an important process
involved in wound healing, embryonic development and cancer
metastasis. Chemotaxis also provides a window into mechanisms of
information processing by chemical circuitry inside single cells.
Characterizing the behavior of a complex regulatory circuit or sensory
system requires precise measurement of response and precise control of
input signals. The proposed work will have important consequences for
basic biology of control of cellular movement, for finding ways to
diagnose and control the tendencies of cancer cells to metastasize and
for understanding the chemotactic mechanisms underlying wound healing.
Previous experimental studies of chemotaxis have controlled either the
temporal or the spatial characteristics of the chemoattractant
stimulus, but not both at once. Similarly, theoretical studies rarely
consider both the gradient sensing problem and the temporal adaptation
problem in the same model. The resulting proliferation of models can
only be constrained by testing both their spatial and temporal aspects
in a unified framework. The experimental techniques to be used will
allow delivery of chemotactic stimuli with precisely tailored spatial
and temporal characteristics to single cells and populations of cells.
The mathematical and computational methods proposed will afford
testable predictions in order to distinguish competing models for the
chemical circuitry underlying cellular decision-making. By performing
single cell psychophysics, i.e. by testing cells at the thresholds
where they can just reliably distinguish spatiotemporal stimuli, and
by comparing the results with a priori estimates of discriminability
based on information theory and stochastic modeling of spatially
distributed chemical networks, it will be possible critically to
assess theoretical models of internal cellular mechanisms.
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