COntrol of
GEnomic,
Nanotech and
Telerobotic Systems Research
Lab
University of Washington
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University of Washington
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Intracellular Sensors of Metabolites in Single Living Cells Instrumentation for Signal Acquisition and Processing From Intracellular Sensors Algebraic Systems Models of DNA Sequence/Structure Relationships Algebraic Systems Models of Transcription Factor Binding Sites Control of Telerobotic Surgical Systems Control of Interconnected Systems with Randomly-Varying Communication Delays Multiscale Modeling and Control Mathematical Systems Modeling and Computer Simulation of Genetic Circuits, Transcription and Translation
Since the metabolome is the end result of gene expression, it comprises the cell's response to genetic and environmental changes. As such, the metabolome is a diagnostic tool for disease. Time-course information about cell dynamics (ie, how cells reach a particular state, and how they change over time) are important for understanding gene function. This project will use experimentally obtained data, as well as information from the literature, as the basis for the development of mathematical models and computer simulations of genetic circuits, transcription and translation processes, and other aspects of functional genomics. Intracellular Sensors of Metabolites in Single Living Cells A variety of techniques and instrumentation exist to study cellular processes in the post-genomic era. However, existing methods have significant limitations (e.g. poor sensitivity, or only applicable to cell extracts). A solution to these problems is an intracellular biosensor, constructed by integrating pre-existing biological components into a functional nanoscale system. This work is being accomplished using the mathematical methods of dynamical systems analysis, control systems engineering, molecular cloning, and the single cell analysis capabilities of the UW Microscale Life Sciences Center (MLSC). The specific task at hand is to develop a plasmid-based sensor that can obtain a time course of measurements of a single metabolite, in intact living cells (E. coli). The general purpose of this research is to develop control theory for nanoscale systems. The design, construction and testing of the intracellular biosensor provides the context for the measurement of dynamic processes of gene and protein expression. Instrumentation for Signal Acquisition and Processing From Intracellular Sensors This work involves the fabrication of an optically transparent microfluidic device to contain a single living cell for microscopic examination. This device collects light emitted by the target cell, in response to the intracellular metabolite concentration. This hardware, in combination with the intracellular sensors, will provide time course measurements of a metabolites in prokaryotes. This dynamic response data in single living cells can be used to construct mathematical models of aspects of functional genomics dynamics. Algebraic Systems Models of DNA Sequence/Structure Relationships In this work,
it is demonstrated that an algebraic systems model can be constructed to relate
the base pair sequence to certain
DNA structural features. In addition to the one-dimensional information used to
produce proteins, the DNA molecule also carries information in its
three-dimensional structure, which influences the binding of specific proteins
to gene control regions along the helix. In prior work, an empirically derived
model of DNA structure was translated into an algebraic systems representation.
This dynamic system representation allows for the prediction of local variations
of DNA helical parameters, with the base pair sequence (as one goes from one end
of the helix to the other) considered as the system input signal and geometric
features of the DNA molecule (at each location along the helix) considered as
the output. In this work it has been shown that this model could be inverted to
solve for the DNA sequence corresponding to a sequence of desired structural
variation. Simulation of both the inverse and forward systems is easily
implemented on a microcomputer. The inverse system has potential use as a tool
in designing sequences of DNA with desired geometrical structures (which
influence specific biochemical and genetic activity). More recently, methods
have been developed for identifying algebraic systems models for other sequence
dependent properties of DNA from data set Algebraic Systems Models of Transcription Factor Binding Sites In the this work, the techniques (described above) will be used to identify models of sequence dependent binding rates of transcription factors and invert these models to solve for the required sequence to realize a desired binding rate. The goal of this project is to create a database that can be used as a parts list for the design of genetic circuits. Genetic circuits are mainly controlled through transcription factors which can act as an activator or an inhibitor for one or more genes. The transcription factors are in turn activated or inhibited by other molecules and proteins. Thus expression of genes can be controlled by the presence of certain molecules and proteins and by the amounts of the transcription factors. This database will contain chemical data describing the binding of transcription factors with their effector molecules (if any) and DNA sequences. This type of data is a critical factor in the understanding of gene expression, and will be useful in the design of genetic circuits within a cell. The project will initially focus on transcription factors present in E. coli. This database will have a web interface allowing users to input and view data in the database. This web interface is being written in PHP which is a server side scripting language. The database itself will be implemented in MySQL. Control of Telerobotic Surgical Systems This work is directed towards the coordinated control of telesurgery systems, involving one or more surgeons operating remotely on a patient, via robotic-assisted surgery. The system includes haptic feedback, and communication channels that may have delays and bandwidth limitations. This work is in cooperation with the Biorobotics Laboratory at UW, and colleagues at the UW School of Medicine. Control of Interconnected Systems with Randomly-Varying Communication Delays This work is directed towards the coordinated control of interconnected systems where the communication channels between systems have significant, random, time-varying time delays. This requires each system to have a certain degree of local intelligence, as well as the ability to model the behavior of some or all of the other systems. We care considering a macro-scale application of this work--telerobotics for remotely assisted surgery. In addition, we are developing theory for situations where there are large numbers of self-organizing (or self-assembling) systems--such as in nano-biological applications. |
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Copyright 2006
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