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Title page for ETD etd-11212016-091700


Type of Document Dissertation
Author Nguyen, Thuy Tuong
Author's Email Address thuy.t.nguyen@vanderbilt.edu
URN etd-11212016-091700
Title Oxidative stress in C. elegans: Discovery of a mechanistic role for gamma-ketoaldehyde lipid peroxidation products in the Free Radical Theory of Aging
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
John Oates Committee Chair
L. Jackson Roberts, II Committee Member
Michael Aschner Committee Member
Michael Freeman Committee Member
Sean Davies Committee Member
Keywords
  • isoketals
  • aging
  • Caenorhabditis elegans
  • sirtuins
  • isoprostanes
Date of Defense 2016-08-19
Availability unrestricted
Abstract
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 Alzheimer’s 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 SA’s 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, SA’s 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 SA’s complete lifespan and healthspan extension.
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