Protein abundance levels are controlled through regulatory processes that govern protein synthesis and degradation. Although translational control is now a widely appreciated mechanism for regulating gene expression and proteome remodeling, a systems-level relationship between translational regulation and cellular physiology remains largely unexplored. The overarching objective of this project is to discover the mechanisms that lead to alterations in proteome flux and predict their responses to dynamic changes in the environment. This objective will be pursued through three aims. First, we will investigate how the availability of key components of the translational apparatus, such as ribosomes, tRNAs and initiation factors, are balanced with the transcriptome and proteome composition depending on a specific static carbon source. This will allow us to develop detailed mathematical models that link global translation, transcription and cell physiology. The predictions of the models can be tested by artificially perturbing the transcription-translation balance. Second, we will study the global feedback mechanisms by which the cell adapts its translational capacity to shifts in the carbon source experimentally, while in parallel extending our mathematical models to integrate the regulatory mechanisms linking carbon source and growth rate with a systems-view of the translation system. We will investigate, using experiments and mathematical models, how differences in the adaptation time of the various components of the translational machinery, proteome and mRNA composition to a fluctuating carbon source affect the cell's translational capacity, and hence, how the cell's global feedback mechanisms respond to dynamic and stochastic changes in the carbon source. Finally, we will build a quantitative mathematical model of proteome flux using a combination of quantitative proteomics and mathematical modeling. We will quantify key parameters of proteome flux including protein translation rate, protein degradation rate, mRNA abundance, and protein abundance. This will be done in both rapidly cycling cells and non-dividing neurons to determine how proteome flux is re-wired in post-mitotic cells. We will use serum starvation as a means to limit nutrients and measure alterations in proteome flux upon nutrient withdrawal and replenishment. We will also investigate dynamics in proteome flux upon mTOR inhibition as a pharmacological means to mimic nutrient deprivation. This will allow for deterministic modeling of how proteome resource allocation is altered, in two divergent cell types, upon nutrient limitation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM085764-09
Application #
9520171
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2010-09-18
Project End
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Cooper, Robert; Tsimring, Lev; Hasty, Jeff (2018) Microfluidics-Based Analysis of Contact-dependent Bacterial Interactions. Bio Protoc 8:
Martinez-Corral, Rosa; Liu, Jintao; Süel, Gürol M et al. (2018) Bistable emergence of oscillations in growing Bacillus subtilis biofilms. Proc Natl Acad Sci U S A 115:E8333-E8340
Zhang, Wei; Bojorquez-Gomez, Ana; Velez, Daniel Ortiz et al. (2018) A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. Nat Genet 50:613-620
Dai, Xiongfeng; Zhu, Manlu; Warren, Mya et al. (2018) Slowdown of Translational Elongation in Escherichia coli under Hyperosmotic Stress. MBio 9:
Muse, Evan D; Yu, Shan; Edillor, Chantle R et al. (2018) Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. Proc Natl Acad Sci U S A 115:E4680-E4689
Bui, Nam; Huang, Justin K; Bojorquez-Gomez, Ana et al. (2018) Disruption of NSD1 in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation. Mol Cancer Ther 17:1585-1594
Huang, Justin K; Carlin, Daniel E; Yu, Michael Ku et al. (2018) Systematic Evaluation of Molecular Networks for Discovery of Disease Genes. Cell Syst 6:484-495.e5
Ozturk, Kivilcim; Dow, Michelle; Carlin, Daniel E et al. (2018) The Emerging Potential for Network Analysis to Inform Precision Cancer Medicine. J Mol Biol 430:2875-2899
Yan, Jian; Chen, Shi-An A; Local, Andrea et al. (2018) Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell Res 28:204-220
Antonova-Koch, Yevgeniya; Meister, Stephan; Abraham, Matthew et al. (2018) Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science 362:

Showing the most recent 10 out of 207 publications