Gene regulatory networks lay at the foundation of biological function and are responsible for driving the diverse cellular tasks required to sustain life. Developing a comprehensive description of cellular function in healthy and diseased states will require a precise quantitative understanding of the dynamics of the underlying interactions. This project will address this need by developing and experimentally validating computational models with predictive capabilities that can be used to understand the complexities of gene regulation in model organisms.
Each aim will investigate a particular dynamic behavior, using a combination of modeling and experimentation to design a synthetic network that mimics a natural system, build the network and ensure that it meets the general design goals, and re/ne the computational model by experimentally testing its predictions and assumptions. The /rst aim will probe the behavior of two synthetic clock networks, in order to elucidate the key properties that de/ne their dynamic behavior. New microbial strains will be developed to explore and test predictions of the oscillatory response to changes in degradation rate and copy number of the network components.
The second aim will investigate the use of biological clocks to coordinate behavior across a population of independent organisms. Modeling will be used to predict the network response to various driving and coupling mechanisms, and the synthetic clocks will be coupled to native pathways to investigate the possibilities of oscillatory entrainment and synchronization.
The third aim proposes to construct synthetic signaling networks that can process and output pulsatile signals. A model will be developed and re/ned to describe the mechanisms of basic information processing at the single-cell level. In the /nal aim, experience with the synthetic microbial networks in the /rst three aims will be applied to develop several genetic circuits in mammalian cells. While many of the basic principles of gene expression should be conserved, the process of developing similar functionality in mammalian cells will likely yield insight into how the particular cellular environment a.ects gene regulation. Each network will be monitored with 0uorescence microscopy at the single-cell level using customized micro0uidic devices. These studies will provide crucial insight into several of the fundamental regulatory motifs that are essential for the propagation of life. PUBLIC HEALTH REVEVANCE: The survival of cells depends on their ability to carry out diverse cellular tasks such as driving the cell division cycle, responding to unpredictable environmental changes, and mounting an appropriate defense against stress. Many diseases arise as the result of individual genes or gene regulatory modules that fail to perform a speci/c task, leading to a breakdown of overall cellular viability. The central goal of this proposal is to construct, study, and model novel synthetic gene circuits that mimic the functionality of native networks, in order to develop a precise quantitative understanding of the dynamic interactions that underlay essential biological functions.
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