Cystic fibrosis (CF) is a debilitating, multi-organ, autosomal recessive disease caused by mutations leading to absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) in epithelial cells. Chronic pulmonary disease, characterized by excessive inflammation and recurrent infections, is the primary source of morbidity and mortality in individuals with CF. Altered polyunsaturated fatty acid (PUFA) biosynthesis, resulting in increased metabolism of linoleic acid (LA) to arachidonic acid (AA), plays a key role in CF pathophysiology. Increased AA biosynthesis contributes to excessive inflammation in the lungs of individuals with CF. The mechanism by which absence of functional CFTR leads to aberrant PUFA biosynthesis has been elusive. This dissertation is the first delineation of a pathway linking PUFA metabolism to CFTR. Through studies in human bronchial epithelial cells, this dissertation demonstrates that absence of functional CFTR leads to increased activation of AMP-activated protein kinase (AMPK) by calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ). Elevated AMPK activity leads to increased expression and activity of Δ6-desaturase (Δ6D) and Δ5-desaturase (Δ5D). Increased activity of Δ6D and Δ5D results in increased metabolism of LA to AA.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07222014-114609 |
| Date | 04 August 2014 |
| Creators | Umunakwe, Obinna C. |
| Contributors | Larry L. Swift, Timothy S. Blackwell, W. Gray Jerome, P. Anthony Weil, Michael Laposata, Adam C. Seegmiller |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07222014-114609/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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