Insights into NF-[kappa] B signaling from single-cell dynamics
Abstract/Contents
- Abstract
- The mammalian immune response is a striking example of many cells working in concert to produce a coherent, complex behavior. The first steps in the immune response are orchestrated by the innate immune system, and one particularly important protein is the transcription factor nuclear factor (NF)-[kappa] B. To better characterize the signaling events of innate immunity at the level at which they start, we have developed a platform to monitor the dynamics of NF-[kappa] B signaling in live, individual cells. This thesis presents three studies that use live-cell imaging, quantitative analysis, and computational modeling to reveal novel insights into how the NF-[kappa] B network functions. In the first study, we investigate how single mammalian cells respond to different concentrations of the signaling molecule tumor necrosis factor (TNF), and how they relay information to the gene expression programs by means of NF-[kappa] B. We find, in contrast to population-level studies, that the activation is heterogeneous and is a digital process at the single-cell level. Next, we focus on lipopolysaccharide (LPS), a molecule found in the outer membrane of gram-negative bacteria that strongly activates NF-[kappa] B. We find that different sources and preparations of LPS induce markedly different dynamics of NF-[kappa] B. Finally, studies of signal transduction often focus on how responses to stimuli differ, and yet the network's most essential dynamic features are probably invariant across stimuli. To identify invariant dynamic features in the NF-[kappa] B network, we treated cells with a broad panel of stimuli. Most properties of the dynamics varied with stimulus type or concentration, but one property had an invariant distribution: the period of NF-[kappa] B's oscillations between cytoplasm and nucleus. Contrary to existing theory of NF-[kappa] B dynamics, this invariance is only observed in the population; individual cells vary significantly. Overall, this work underscores the dynamic nature of biological systems, and highlights how quantitative measurements in single cells can advance our understanding of such systems.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2013 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Hughey, Jacob Joseph |
|---|---|
| Associated with | Stanford University, Department of Bioengineering. |
| Primary advisor | Covert, Markus |
| Thesis advisor | Covert, Markus |
| Thesis advisor | Lin, Y. K. (Yu-Kweng), 1923- |
| Thesis advisor | Quake, Stephen Ronald |
| Advisor | Lin, Y. K. (Yu-Kweng), 1923- |
| Advisor | Quake, Stephen Ronald |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Jacob Joseph Hughey. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Ph.D. Stanford University 2013 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2013 by Jacob Joseph Hughey
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...