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You searched for +publisher:"Vanderbilt University" +contributor:("Amy S. Major, Ph.D."). Showing records 1 – 2 of 2 total matches.

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Vanderbilt University

1. Spurlock III, Charles Floyd. Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints.

Degree: PhD, Microbiology and Immunology, 2014, Vanderbilt University

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. Advisors/Committee Members: Subramaniam Sriram, M.B., B.S. (committee member), Jonathan M. Irish, Ph.D. (committee member), Amy S. Major, Ph.D. (committee member), Andrew J. Link, Ph.D. (chair), Thomas M. Aune, Ph.D. (committee member).

Subjects/Keywords: methotrexate; autoimmune disease; inflammation; rheumatoid arthritis; cell cycle checkpoints; c-Jun-N-terminal kinase; p53; tetrahydrobiopterin; long non-coding RNA

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Spurlock III, C. F. (2014). Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;

Chicago Manual of Style (16th Edition):

Spurlock III, Charles Floyd. “Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 19, 2019. http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;.

MLA Handbook (7th Edition):

Spurlock III, Charles Floyd. “Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints.” 2014. Web. 19 Apr 2019.

Vancouver:

Spurlock III CF. Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2019 Apr 19]. Available from: http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;.

Council of Science Editors:

Spurlock III CF. Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;


Vanderbilt University

2. Katrangi, Waddah. The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis.

Degree: PhD, Pathology, 2014, Vanderbilt University

The primary cause of morbidity and mortality in cystic fibrosis is progressive pulmonary disease, an important component of which is a hyperactive inflammatory response, the mechanisms of which are not completely understood. Previous studies have highlighted alterations in polyunsaturated fatty acid and eicosanoid metabolism in cystic fibrosis airway epithelial cells leading to increased arachidonic acid and its metabolites, the pro-inflammatory leukotrienes and prostaglandins. This work tests the hypothesis that these underlying metabolic abnormalities play an important role in the excessive inflammatory response. Using airway epithelial cell culture models of cystic fibrosis, we demonstrate that there is increased release of AA in response to stimulation in CF cells. Additionally, we show that enzymes of fatty acid and eicosanoid metabolism, including Δ6-desaturase, cytosolic phospholipase A2, cyclooxygenase-2, microsomal PGE2 synthase, and 5-lipoxygenase, are upregulated in cystic fibrosis cells compared to wild-type counterparts. These increases are exaggerated when the cells are stimulated with products of Pseudomonas aeruginosa culture, leading to increased production of PGE2 and LTB4 and the pro-inflammatory cytokines IL-6 and IL-8. Inhibition of the LTB4 synthesis pathway at any of multiple points results in blunting of both cyclooxygenase-2 expression and IL-6 and IL-8 production, while inhibition of cyclooxygenase-2 itself results in only minor suppression of cytokine production. Similar results are seen with docosahexaenoic acid, an anti-inflammatory n-3 fatty acid. Taken together, these results indicate that fatty acid and eicosanoid metabolic abnormalities that are intrinsic to epithelial cells in cystic fibrosis, particularly the LTB4 synthesis pathway, may play an important role in the hyperactive inflammatory response characteristic of this disease. Advisors/Committee Members: Michael Laposata, M.D., Ph.D. (committee member), Claus Schneider, Ph.D. (committee member), Larry L. Swift, Ph.D. (committee member), Amy S. Major, Ph.D. (chair), Adam C. Seegmiller, M.D., Ph.D. (committee member).

Subjects/Keywords: arachidonic acid; eicosanoid; fatty acid; inflammation; cystic fibrosis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Katrangi, W. (2014). The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-06242014-123859/ ;

Chicago Manual of Style (16th Edition):

Katrangi, Waddah. “The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 19, 2019. http://etd.library.vanderbilt.edu/available/etd-06242014-123859/ ;.

MLA Handbook (7th Edition):

Katrangi, Waddah. “The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis.” 2014. Web. 19 Apr 2019.

Vancouver:

Katrangi W. The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2019 Apr 19]. Available from: http://etd.library.vanderbilt.edu/available/etd-06242014-123859/ ;.

Council of Science Editors:

Katrangi W. The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://etd.library.vanderbilt.edu/available/etd-06242014-123859/ ;

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