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The Altschuler & Wu laboratory
Location :UT Southwestern Medical Center, Dallas, Texas, USA.
Our lab investigates mechanisms underlying the spatial and temporal organization of cells using a combination of experimentation and modeling.
We are developing image-analysis based methods that allow us to study how cellular organization is dynamically regulated in response to environmental perturbations. Our approach combines robotic liquid handling, high-throughput fluorescence microscopy, automated image analysis, statistics, and mathematical modeling to analyze changing patterns of morphology and protein localization at an individual cell level. We applied our methods to cells treated with a selection of medicines and toxins over a wide range of dosages. Cells were stained with probes for DNA and a variety of proteins. Multidimensional measures, based on changes in protein localization and cellular morphology, were used to generate phenotypic profiles for each drug. These profiles may be visualized in a manner analogous to transcript profiles (rightmost panel below).
In many cases, drugs with similar profiles in our study were known to have the same biochemical targets, showing that our method succeeded in characterizing drug effects at a biological level. Thus, our method may be useful for inferring drug mechanism of previously uncharacterized compounds. Cytological profiling is relatively inexpensive, provides large amounts of biological information complementary to other high-throughput profiling technologies, and effectively brings microscopy into the "omics" era.
The ability to polarize is found in nearly all cell types and is essential for physiological processes as diverse as cell differentiation, cell motility, neuronal growth, and immune responses. Polarization can occur either in response to an internal or external spatial signal, or spontaneously in the apparent absence of pre-existing spatial cues. Interestingly, many mechanisms leading to polarization, such as those involving actin- and scaffolding-dependent feedback, appear to be conserved across a broad range of cell types. We currently lack a quantitative understanding of how these different mechanisms work together to create sharply defined spatial patterns, analogous to MAP-kinase cascades creating ultra-sensitive temporal switches.
We are working to dissect, disentangle, and reassemble mechanisms of polarization in the yeast budding and neutrophils chemotaxis pathways, using a close collaboration between modeling and experimentation. The mathematical tools we use to study polarity formation and maintenance draw upon theory from reaction-diffusion equations, geometry, and stochastic processes. Validation of model predictions require the development of automated image processing algorithms and analytical techniques to extract information from movies of polarizing yeast and fast-moving neutrophils.