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Principal Investigator: Judit Villen
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $419,850
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Protein phosphorylation is the most important and most extensively studied mechanism by which cells rapidly
sense signals, transduce signals, and execute decisions. Protein phosphorylation provides a means to
dynamically regulate protein function, is integral to all cellular processes, and abnormal phosphorylation is
associated with many diseases. In our previous research, we developed and applied experimental and
computational phosphoproteomics methods to systematically interrogate the signaling network and reveal its
architecture and design principles. Our rigorous research delivered reproducible methods, which are essential
to analyze phosphoproteomes in multi-perturbation studies. Our applications delivered knowledge that is
crucially important to understand why different cell types respond differently to the same stimuli to accomplish
different functions.
Building on the methods we developed and knowledge acquired, we propose to focus our research for the next
5 years on the functional aspects of protein phosphorylation, addressing the outstanding question of how
phosphorylation regulates the organization of the cellular proteome. We will expand our studies in multiple
directions that represent the next frontier in signaling biology. First, we will identify phosphosites that are
relevant to protein functions at the proteomic scale. Second, we will study how phosphorylation regulates the
multi-level organization of the cellular proteome from transient protein interactions to subcellular organelles.
Third, we will study the differences in signaling of morphologically distinct cellular phenotypes. Fourth, we will
develop methods to include phosphorylation of tyrosine and histidine in phosphoproteomic studies. Fifth, we
will assess the impact of mutations on protein functions at the proteomic scale.
To achieve these goals, we will combine mass spectrometry-based proteomics, high throughput biochemistry,
molecular biology, advanced microscopy, cell sorting, and computational and statistical methods, placing a
strong emphasis on expanding the capabilities of current proteomic methods. This research will deliver new
methods and a wealth of knowledge of protein phosphorylation in a spatial, temporal, and functional context;
which can be expanded in many new directions. Our discoveries on the basic functioning and regulation of
proteins can have an immediate translational impact by informing us about the functional consequences of
mutations and changes in phosphorylation in disease states.
Terms: <Address><Architecture><Biochemistry><Biological Chemistry><Biology><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Isolation><Cell Physiology><Cell Process><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Communicable Diseases><Computing Methodologies><DNA Molecular Biology><Disease><Disorder><Engineering / Architecture><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Goals><Histidine><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intracellular Communication and Signaling><Knowledge><Knowledge acquisition><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Metabolic Diseases><Metabolic Disorder><Methods><Microscopy><Molecular Biology><Morphology><Mutation><Nervous System Diseases><Nervous System Disorder><Neurologic Disorders><Neurological Disorders><Organelles><Phenotype><Phosphorylation><Protein Phosphorylation><Proteins><Proteome><Proteomics><Regulation><Reproducibility><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Statistical Methods><Stimulus><Subcellular Process><Thesaurismosis><Tyrosine Phosphorylation><Variant><Variation><biological signal transduction><cell sorting><cell type><computational methodology><computational methods><computer based method><computer methods><computing method><design><designing><frontier><genetic condition><genetic disorder><genome mutation><insight><malignancy><metabolism disorder><neoplasm/cancer><neurological disease><phospho-proteomics><phosphoproteomics><protein function><social role><statistic methods><translational impact>