This application requests support for the establishment of the National Resource for Cell Analysis and Modeling. The Resource will be housed within, and will be the principal venture, of the Center for Biomedical Imaging Technology (CBIT) at the University of Connecticut Health Center. The Resource will contain state of the art facilities for studying living cells and will develop a new technology, the Virtual Cell, for analyzing and synthesizing this knowledge. The Virtual Cell is a general framework for modeling cell biological processes. It approaches the problem by associating biochemical and electrophysiological data describing individual reactions, with experiment microscopic image data describing their subcellular locations. Individual processes are integrated within a physical and computational infrastructure that will accommodate any molecular mechanism. This will computational technology will be developed within a research center that is fully equipped for microscopic studies of living cells, will assure that experiment and theory will drive each other synergistically. Consistent with this philosophy, the research plan for the technology development is divided into two projects centered on theory and two that are primarily experimental. Computational Infrastructure addressed the issues of: (1) layering the cell biological models on a transparent physical and mathematical foundation; (2) implementing the numerical methods in a distributed parallel computing environment; (3) creating a user interface for model building that is modular, remotely accessible, and readily adaptable to a database of images and reaction mechanisms. Mathematic and Physical Analysis of Cell Biological Processes has 3 goals: the formulation of generalized mathematical descriptions of the elementary physical processes underlying the myriad of cell biological mechanisms; the development and validation of efficient numerical methods, development of rigorous methods for building and refining models from experimental data. Calcium Dynamics in Differentiated Neuroblastoma Cells and Cardiomyocytes aims to elucidate intracellular calcium signaling in these cells via a systematical marriage of experiment and modeling approaches: these studies will be used as a testbed for the Virtual Cell technology and will drive improvements and expansions. The last project, Intracellular RNA Trafficking, aims to use microscopic imaging and modeling to understand the series of events in which RNA is exported from the nucleus, packaged into granules, transported to remote regions of a cell, and translocated by the protein synthetic apparatus; this project will require new extensions of the Virtual Cell to incorporate the dynamics of intracellular supramolecular structures within the overall physical framework. A series of 11 collaborative projects are described with investigators from around the U.S. and Europe. Service, training, and dissemination activities of the Resource will all build upon the pre- existing facilities and track record of CBIT.
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