Network analysis and drug target identification in mast cells
Abstract/Contents
- Abstract
- Target identification is both a critical and difficult step in the drug discovery process. A novel approach is presented here that utilizes flow cytometry to: 1) identify small molecule signaling network probes, and 2) characterize the diverse network activation states they induce. Signaling events across the network are compared to functional responses to determine the way in which each signaling node influences a given function. Nodes that accurately predict cellular functions that drive disease are promising drug targets. The approach was applied to mast cells to determine which signaling molecules best predicted the degranulation, eicosanoid release, and cytokine secretion induced by stimulation of the cells with IgE and specific antigen crosslinking. Erk and Akt phosphorylation best predicted degranulation; Erk and cJun phosphorylation best predicted eicosanoid release; and Akt phosphorylation alone best predicted cytokine secretion. The results confirmed several known aspects of mast cell IgE-dependent signaling and revealed unknown associations to be tested in future work -- notably, that the cJun pathway plays a role in eicosanoid production and that the Akt pathway is a critical integration point for transcription of most or all cytokine genes. Overall, the results suggest that Erk and Akt are the most promising targets in the IgE signaling network for development of mast cell stabilizing drugs.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Copyright date | 2011 |
| Publication date | 2010, c2011; 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Clutter, Matthew Ryan |
|---|---|
| Associated with | Stanford University, Department of Immunology. |
| Primary advisor | Nolan, Garry P |
| Thesis advisor | Nolan, Garry P |
| Thesis advisor | Chen, James Kenneth |
| Thesis advisor | Davis, Mark M |
| Thesis advisor | Galli, Stephen J |
| Advisor | Chen, James Kenneth |
| Advisor | Davis, Mark M |
| Advisor | Galli, Stephen J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Matthew Ryan Clutter. |
|---|---|
| Note | Submitted to the Department of Immunology. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Matthew Ryan Clutter
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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