The role of the PDGFR and c-FMS signaling pathways in autoimmune demyelination
Abstract/Contents
- Abstract
- Multiple Sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system characterized by demyelination and variable axonal loss. Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of MS. Imatinib mesylate (imatinib), sorafenib, and GW2580 are tyrosine kinase inhibitors (TKIs) developed to treat diverse types of cancers. This thesis demonstrates that Imatnib and Sorafenib, two PDGFR inhibitors and GW2580, a specific Fms inhibitor, can prevent and treat MOG-induced experimental autoimmune encephalomyelitis (EAE). My observations suggest that the c-Fms and PDGFR tyrosine kinase signaling pathways play a central role in the pathogenesis of EAE and MS. I believe that c-Fms primes macrophages to produce TNF and that PDGFR induces astrocytes to proliferate, which are cellular responses contributing to autoimmune demyelination in multiple sclerosis. Chapter 1 provides a general introduction to MS and EAE and the role different cell types of the immune system play in disease pathogenesis, paying particular attention to the role of macrophages and astrocytes. Chapter 2 describes in further detail the different functions mediated by MCSF in macrophages and how these are tied to the pathology of MS. In this chapter, the experiments performed to determine whether c-Fms inhibition using tyrosine kinase inhibitors could have an effect on pathogenic macrophage functions are described. Chapter 3 focuses on the immune functions of astrocytes, emphasizing those believed to be mediated by PDGFR signaling, and the experiments performed to test the effects of tyrosine kinase inhibitors on PDGFR-mediated astrocyte functions. Chapter 4 concludes with a discussion of the results and future directions for the use of tyrosine kinase inhibitors for the screening of potential targets involved in the pathogenesis of autoimmune diseases.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Crespo Diaz, Oliver | |
|---|---|---|
| Associated with | Stanford University, Program in Immunology | |
| Primary advisor | Robinson, William (William Hewitt) | |
| Thesis advisor | Robinson, William (William Hewitt) | |
| Thesis advisor | Fathman, C. Garrison | |
| Thesis advisor | Steinman, Lawrence | |
| Thesis advisor | Utz, Paul | |
| Advisor | Fathman, C. Garrison | |
| Advisor | Steinman, Lawrence | |
| Advisor | Utz, Paul |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Oliver Crespo. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2011. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Oliver Crespo Diaz
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