dc.creator | Spurlock III, Charles Floyd | |
dc.date.accessioned | 2020-08-21T21:19:10Z | |
dc.date.available | 2016-03-21 | |
dc.date.issued | 2014-03-21 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03212014-091439 | |
dc.identifier.uri | http://hdl.handle.net/1803/10993 | |
dc.description.abstract | Rheumatoid arthritis is the most common serious autoimmune disease affecting almost one percent of the human population worldwide. Methotrexate is the most commonly used disease-modifying agent in patients with rheumatoid arthritis. Despite decades-long experience with the use of methotrexate in this disease, the mechanisms responsible for its activity in rheumatoid arthritis are not very well understood. Through a series of biochemical approaches and in vivo studies in patients with rheumatoid arthritis, we have defined two novel pathways contributing to the anti-inflammatory effects of methotrexate in T cells. The first pathway is dependent upon blockade of tetrahydropbiopterin biosynthesis resulting in increased activation of c-Jun-N-terminal kinase, restoration of cell cycle checkpoint deficiencies, and reduced levels of nuclear factor kappa B, a master regulator of inflammation. Finally, we also discovered that methotrexate induces expression of the long, intergenic non-coding RNA, lincRNA-p21. Independent of methotrexate-mediated blockade of tetrahydrobiopterin and increased activity of c-Jun-N-terminal kinase, induction of lincRNA-p21 by methotrexate also reduces indices of inflammation via blockade of nuclear factor kappa B activity. Thus, multiple pathways are responsible for the immunomodulatory effects of methotrexate in the treatment of rheumatoid arthritis. | |
dc.format.mimetype | application/pdf | |
dc.subject | methotrexate | |
dc.subject | autoimmune disease | |
dc.subject | inflammation | |
dc.subject | rheumatoid arthritis | |
dc.subject | cell cycle checkpoints | |
dc.subject | c-Jun-N-terminal kinase | |
dc.subject | p53 | |
dc.subject | tetrahydrobiopterin | |
dc.subject | long non-coding RNA | |
dc.title | Methotrexate and Rheumatoid Arthritis:
At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints | |
dc.type | dissertation | |
dc.contributor.committeeMember | Subramaniam Sriram, M.B., B.S. | |
dc.contributor.committeeMember | Jonathan M. Irish, Ph.D. | |
dc.contributor.committeeMember | Amy S. Major, Ph.D. | |
dc.contributor.committeeMember | Thomas M. Aune, Ph.D. | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Microbiology and Immunology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2016-03-21 | |
local.embargo.lift | 2016-03-21 | |
dc.contributor.committeeChair | Andrew J. Link, Ph.D. | |