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Fontan-Lozano, A., Saez-Cassanelli, J.L., Inda, M.C., Santos-Arteaga, M.D.L., Sierra-Dominguez, S.A., Lopez-Lluch, G., Delgado-Garcia, J.M., and Carrion, A.M. (2007). Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B Subunits of the NMDA receptor. Journal of Neuroscience 27, 10185-10195.
Frye, R.A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273, 793-798.
Gaitanaki, C., Konstantina, S., Chrysa, S., and Beis, I. (2003). Oxidative stress stimulates multiple MAPK signalling pathways and phosphorylation of the small HSP27 in the perfused amphibian heart. J Exp Biol 206, 2759-2769.
Gredilla, R., Sanz, A., Lopez-Torres, M., and Barja, G. (2001). Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J 15, 1589-1591.
Guarente, L. (2005). Calorie restriction and SIR2 genes--towards a mechanism. Mech Ageing Dev 126, 923-928.
Guyton, K.Z., Liu, Y., Gorospe, M., Xu, Q., and Holbrook, N.J. (1996). Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem 271, 4138-4142.
Hamilton, M.L., Van Remmen, H., Drake, J.A., Yang, H., Guo, Z.M., Kewitt, K., Walter, C.A., and Richardson, A. (2001). Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 98, 10469-10474.
Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S.J., and Kenyon, C. (2007). Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95-110.
Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J Gerontol 11, 298-300.
Hauck, S.J., and Bartke, A. (2001). Free radical defenses in the liver and kidney of human growth hormone transgenic mice: possible mechanisms of early mortality. J Gerontol A Biol Sci Med Sci 56, B153-162.
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P.C., Cervera, P., and Le Bouc, Y. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187.
Object Description
| Title | Roles of SIRT1 in neuronal oxidative damage and brain function |
| Author | Li, Ying |
| Author email | lying@usc.edu; yingraceli@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-09-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Baudry, Michel Pike, Christian J. Madigan, Stephen A. |
| Abstract | Aging is a common phenomenon of multiple organisms. In humans aging is frequently accompanied by cognitive decline and occurrence of neurodegenerative diseases which reduce the quality of life and impose financial stress on society. Delaying the aging process, extending life span and decreasing the occurrence of age-related brain function deficit have always been aspirations of human kind. Extensive research has advanced our understanding of the mechanisms underlying aging, among which is the ability of calorie restriction to increase longevity, and the pivotal regulatory roles of insulin/IGF-1 signaling pathway. Some recent studies identified silent information regulator 2 (Sir2; SIRT1 is the mammalian homolog) as a key mediator of the beneficial effects of calorie restriction and this prompted development of SIRT1 activators for human consumption to delay aging and accompanying cognitive decline. However, our laboratory previously showed in yeast that Sir2 can increase stress sensitivity and limit life span extension under certain conditions, calling for more detailed characterization of SIRT1. In the research described in this dissertation I extended this study to the mammalian system and focused on the role of SIRT1 on the health of neurons and brain functions, especially learning and memory.; This dissertation consists of three chapters. In chapter 1 I briefly review some recent progress on aging, oxidative stress, insulin/IGF-1 signaling pathway and learning and memory with emphasis on the involvement of SIRT1 in these processes. In chapter 2 I focused on the role of SIRT1 in oxidative stress in neurons and its mechanisms. I found that SIRT1 inhibition increased resistance to oxidative damage and this effect is partially mediated by a reduction in IGF-I/IRS-2/Ras/ERK1/2 signaling. In chapter 3 I studied the functions of SIRT1 in learning and memory. The experiments showed that deletion of SIRT1 impairs a certain form of synaptic plasticity and reduce performance in several different learning and memory tasks while overexpressing SIRT1 did not substantially affect learning and memory.; Together, my studies reveal that SIRT1 exacerbates neuronal oxidative damage but is essential in learning and memory, indicating that SIRT1 plays multiple roles in aging and brain functions and that caution should be exercised in designing anti-aging or therapeutic approaches that involve targeting SIRT1. |
| Keyword | SIRT1; neurons; brain; oxidative damage; learning and memory |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1723 |
| Contributing entity | University of Southern California |
| Rights | Li, Ying |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LI-2405 |
| Archival file | uscthesesreloadpub_Volume44/etd-LI-2405.pdf |
Description
| Title | Page 134 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 124 Fontan-Lozano, A., Saez-Cassanelli, J.L., Inda, M.C., Santos-Arteaga, M.D.L., Sierra-Dominguez, S.A., Lopez-Lluch, G., Delgado-Garcia, J.M., and Carrion, A.M. (2007). Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B Subunits of the NMDA receptor. Journal of Neuroscience 27, 10185-10195. Frye, R.A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273, 793-798. Gaitanaki, C., Konstantina, S., Chrysa, S., and Beis, I. (2003). Oxidative stress stimulates multiple MAPK signalling pathways and phosphorylation of the small HSP27 in the perfused amphibian heart. J Exp Biol 206, 2759-2769. Gredilla, R., Sanz, A., Lopez-Torres, M., and Barja, G. (2001). Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J 15, 1589-1591. Guarente, L. (2005). Calorie restriction and SIR2 genes--towards a mechanism. Mech Ageing Dev 126, 923-928. Guyton, K.Z., Liu, Y., Gorospe, M., Xu, Q., and Holbrook, N.J. (1996). Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem 271, 4138-4142. Hamilton, M.L., Van Remmen, H., Drake, J.A., Yang, H., Guo, Z.M., Kewitt, K., Walter, C.A., and Richardson, A. (2001). Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 98, 10469-10474. Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S.J., and Kenyon, C. (2007). Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95-110. Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J Gerontol 11, 298-300. Hauck, S.J., and Bartke, A. (2001). Free radical defenses in the liver and kidney of human growth hormone transgenic mice: possible mechanisms of early mortality. J Gerontol A Biol Sci Med Sci 56, B153-162. Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P.C., Cervera, P., and Le Bouc, Y. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187. |
