Highly reactive acyclic levuglandin-like gamma-ketoaldehydes (gamma-KA, isoketals, or IsoKs) are formed as products of the isoprostane pathway of lipid peroxidation. IsoKs are known to covalently adduct ε-amino groups in lysyl residues of proteins, forming stable adducts and intramolecular cross-links. Increased IsoK-lysyl-lactam adducts are found in a number of disease conditions, including atherosclerosis, end-stage renal disease, and Alzheimerâs disease. A selective IsoK scavenger, salicylamine (SA), was developed and tested in Caenorhabditis elegans to probe the pathophysiological processes in IsoK-mediated oxidative injury, and consequently provide the groundwork for the development of new rational therapeutic interventions to limit oxidative damage. Administration of SA extends adult nematode longevity by nearly 56% and prevents multiple deleterious age-related biochemical and functional changes. Testing of a variety of molecular targets for SAâs action revealed the sirtuin SIR-2.1 as the leading candidate. When SA was administered to a SIR-2.1 knockout strain, the effects on lifespan and healthspan extension were abolished. The SIR-2.1-dependent effects of SA were not mediated by large changes in gene expression programs or by significant changes in mitochondrial function. However, expression array analysis did show SA-dependent regulation of the transcription factor ets-7 and associated genes. In ets-7 knockout worms, SAâs longevity effects were abolished, similar to sir-2.1 knockouts. However, SA dose-dependently increases ets-7 mRNA levels in non-functional SIR-2.1 mutant, suggesting that both are necessary for SAâs complete lifespan and healthspan extension.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11212016-091700 |
| Date | 30 November 2016 |
| Creators | Nguyen, Thuy Tuong |
| Contributors | L. Jackson Roberts, II, Michael Aschner, John Oates, Sean Davies, Michael Freeman |
| 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-11212016-091700/ |
| Rights | restrictsix, 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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