Redox regulation of cellular information processing

Linda Kippner

Collaborators: Christine Payne, Yuhong Fan

Funding Source: NIH New Innovator Award, GT-FIRE award, NIEHS, Emory HERCULES Center

Elevated concentrations of extracellular reactive oxygen species (ROS) are hallmarks of inflammation, and decades of medical research have focused on suppression of these molecules to treat pathologies as diverse as rheumatoid arthritis, cancer, and atherosclerosis with mixed results. More recently, researchers have discovered that these same molecules are produced during the course of normal signal transduction. In order to effectively treat inflammation, we must understand these distinct roles for reactive oxygen species. We are developing an innovative research program that will elucidate the role of hydrogen peroxide, a key ROS, in normal cell signaling through computational models and laboratory experiments. This research will lead to a new, quantitative understanding of ROS and facilitate the development of effective antioxidant treatments for inflammation.

This project uses three complementary approaches to evaluate the complex regulatory role of hydrogen peroxide on receptor-induced signaling. First, we are developing computational network models describing redox regulation of proteins in time-dependent manner. Secondly, we are designing new methods to detect oxidative changes on multiple proteins simultaneously. These assays will allow investigation of the relationships between phosphorylation of signal transduction molecules and reversible thiol modifications. Finally, we have created a series of cell lines in which key components of the redox network have been perturbed that demonstrate augmentation and attenuation of receptor signaling. These lines will be used to systematically investigate the efficiency of three receptor networks – a pro-inflammatory cue (TNF-α), anti-inflammatory cue (TGF-β) and antigenic response (TCR) – under different oxidative environments.

 

Related Publications

*Warren, E.A.K., *Netterfield, T.S., Sarkar, S., Kemp, ML, Payne, C.K.. “Spatially-resolved Intracellular Sensing of Hydrogen Peroxide in Living Cells”. Scientific Reports 5:16929, DOI: 10.1038/srep16929, 2015.

Dwivedi, G., Gran, M.A., Bagchi, P., Kemp, M.L. “Dynamic Redox Regulation of IL-4 Signaling”. PLoS Computational Biology DOI:10.1371/journal.pcbi.1004582, 2015.

Prasanphanich, A.F., Arencibia, C.A., Kemp, M.L. “Redox Processes Inform Multivariate Transdifferentiation Trajectories Associated with TGFβ-Induced Epithelial-Mesenchymal Transition”. Free Radical Biology & Medicine, 76:1-13, 2014.

Kippner, L.E., Kim, J., Gibson, G., Kemp, M.L. “Single Cell Transcriptional Analysis Reveals Novel Innate Immune Cell Types”. PeerJ 2:e452; DOI 10.7717/peerj.452, 2014.

Sarkar, S., Payne, C.K., Kemp, M.L. “Conditioned Media Downregulates Nuclear Expression of Nrf2”. Cellular and Molecular Bioengineering, 6(2): 130-137, 2013.

Li, Y., Dwivedi, G., Huang, W., Kemp, M.L., Yi, Y. "Quantification of degeneracy in biological systems for characterization of functional interactions between modules". Journal of Theoretical Biology, 302:29-38, 2012.

Dwivedi, G., Kemp, M.L. "Systemic redox regulation of cellular information processing". Antioxidants & Redox Signaling, 16(4):374, 2012.

Kippner, L.E., Finn, N.A., Shukla, S., Kemp, M.L. "Systemic remodeling of the redox regulatory network due to RNAi perturbations of glutaredoxin 1, thioredoxin 1, and glucose-6-phosphate dehydrogenase". BMC Systems Biology, 13(5): 164, 2011.

Adimora N.J., Jones, D.P., Kemp, M.L. "A model of redox kinetics implicates the thiol proteome in cellular hydrogen peroxide responses". Antioxidants & Redox Signaling, 13(6):731-43, 2010.