Core Projects & Scientists
Core Projects & Scientists
2011 PILOT PROJECT
Probing the Molecular Mechanisms of the Robust EGF-Mediated Transcriptional Response in Cancer Cells
The purpose of this one year career development proposal is to perform several proof-of-concept experiments that demonstrate the feasibility in relating EGFR signaling networks (in terms of protein modification, and nuclear translocation) with dynamic changes in mRNA and miRNA expression. By leveraging information regarding cell signaling and transcription factor protein function we will can perform further targeted functional validation on those transcription factors that are important for mediating transcriptional response to EGF perturbation. When extended to all human transcription factors in the future (using a larger transcription factor antibody panel), we intend to model the protein modification data, the protein localization data, and the mRNA and miRNA expression data as covariates at each time point, and integrate all of the data types into a model that ascribes correlations that can be subsequently be tested for causality via targeted knockdown or other approaches.
2011 PILOT PROJECT
Transcriptional Regulatory Network Sensitivity, Stability and Robustness in Drosophila Circadian Clocks: Solving the Mystery of Temperature Compensation
Circadian clocks are remarkably timekeepers, displaying precise timing over a wide range of temperatures. Genetic analyses have revealed a multiple feedback loop network at the core of circadian pacemakers. Yet the function of these multiple feedback loops remains unclear. We propose that the multiplicity of loops is a requirement for robustness under natural environmental conditions, especially varying temperature. To test this model, we will systematically profile the expression of several clock components from each feedback loop under low and high temperature conditions. These results will provide the high resolution and comprehensive data required to develop quantitative models for circadian network function.
Transcriptional Robustness of Staphylococcus to Host and Environmental Stresses
The goal of this core project is to dissect and model the transcriptional network in Staphylococcus that responds to host and environmental stresses and controls/regulates bacterial antibiotic resistance, virulence, and other properties.
Structure, and Physiological and Evolutionary Robustness of Stress Response Networks in Eukaryotes
This project investigates the structure as well as physiological and evolutionary robustness of the conserved heat-shock response in C. elegans and other species of nematodes. In addition to the heat-shock response, the group studies networks of genes involved in other environmental cues such as heavy metal, UV, nutrient deprivation, osmotic and oxidative stresses. These networks are expected to reveal previously unknown regulatory relationships, identify similarities and differences between networks responsive to different stressors, and uncover conserved and divergent elements of stress responses between distantly related eukaryotes. Finally, the group uses computational and functional comparisons of the cis-regulatory elements of stress response genes from distantly related species of eukaryotes to understand the basic principles of their transcriptional control as well as mechanisms that maintain sensitive and yet highly conserved patterns of gene expression over long periods of evolutionary time.
Dynamics of the Drosophila Segmentation Network, Decoding the Mechanistic Basis of Stability Under Stress and Evolution
This project combines a multi-level approach to investigate the functional basis for robustness in the Drosophila segmentation network genes. A comprehensive network model of transcription factors controlling the segmentation pathway in Drosophila embryogenesis is evaluated by combining genomics and evolutionary approaches. In addition, a mathematical modeling of pattern formation by key genes is used to gain a deeper understanding of mechanisms controlling the robustness of each step in the segmentation pattern formation process.
Drosophila Eye Differentiation: The Yan Network
One of the most well understood transcriptional regulatory networks that responds to cell-cell signaling is the "Yan" network that controls neuronal cell fate in the Drosophila eye. The goal of this core project is to incorporate single cell analysis with predictive mathematical modeling to determine how the Yan transcription factor network specifies distinct cell fates in the developing Drosophila eye. Importantly, the analysis will consider not only the structural scaffold of transcriptional hierarchies and protein-protein interactions on which the network is based, but will also incorporate the complex patterns of post- translational modifications which constitute an essential but poorly understand component of the networks.
Elucidation of Design Principles, Dynamics and Robustness of Gene Regulatory Networks Orchestrating Hematopoietic Cell Fates
This project will elucidate the complex hematopoietic stem cells regulatory networks that give rise to blood and immune cells and understand their dynamics and robustness at the systems level. We will use a combination of approaches including genome-wide expression and chromatin cross-linking analyses, bioinformatic and high-throughput analyses of cis-elements, 3D cultures, and transcription factor perturbations as well as computational and mathematical modeling.
NIGMS