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123
Alt, F.W. (2005). Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2, 67-76.
Cohen, H.Y., Miller, C., Bitterman, K.J., Wall, N.R., Hekking, B., Kessler, B., Howitz, K.T., Gorospe, M., de Cabo, R., and Sinclair, D.A. (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390-392.
de Cabo, R., Furer-Galban, S., Anson, R.M., Gilman, C., Gorospe, M., and Lane, M.A. (2003). An in vitro model of caloric restriction. Exp Gerontol 38, 631-639.
Duan, W., and Mattson, M.P. (1999). Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J Neurosci Res 57, 195-206.
English, J.D., and Sweatt, J.D. (1997). A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272, 19103-19106.
Fabrizio, P., Gattazzo, C., Battistella, L., Wei, M., Cheng, C., McGrew, K., and Longo, V.D. (2005). Sir2 blocks extreme life-span extension. Cell 123, 655-667.
Fabrizio, P., Liou, L.L., Moy, V.N., Diaspro, A., Valentine, J.S., Gralla, E.B., and Longo, V.D. (2003). SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163, 35-46.
Fabrizio, P., Pletcher, S.D., Minois, N., Vaupel, J.W., and Longo, V.D. (2004). Chronological aging-independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae. FEBS Lett 557, 136-142.
Fabrizio, P., Pozza, F., Pletcher, S.D., Gendron, C.M., and Longo, V.D. (2001). Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288-290.
Finkbeiner, S. (2000). CREB couples neurotrophin signals to survival messages. Neuron 25, 11-14.
Firestein, R., Blander, G., Michan, S., Oberdoerffer, P., Ogino, S., Campbell, J., Bhimavarapu, A., Luikenhuis, S., de Cabo, R., Fuchs, C., Hahn, W.C., Guarente, L.P., and Sinclair, D.A. (2008). The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020.
Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., and Tsai, L.H. (2007). Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178-182.
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 133 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 123 Alt, F.W. (2005). Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2, 67-76. Cohen, H.Y., Miller, C., Bitterman, K.J., Wall, N.R., Hekking, B., Kessler, B., Howitz, K.T., Gorospe, M., de Cabo, R., and Sinclair, D.A. (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390-392. de Cabo, R., Furer-Galban, S., Anson, R.M., Gilman, C., Gorospe, M., and Lane, M.A. (2003). An in vitro model of caloric restriction. Exp Gerontol 38, 631-639. Duan, W., and Mattson, M.P. (1999). Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J Neurosci Res 57, 195-206. English, J.D., and Sweatt, J.D. (1997). A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272, 19103-19106. Fabrizio, P., Gattazzo, C., Battistella, L., Wei, M., Cheng, C., McGrew, K., and Longo, V.D. (2005). Sir2 blocks extreme life-span extension. Cell 123, 655-667. Fabrizio, P., Liou, L.L., Moy, V.N., Diaspro, A., Valentine, J.S., Gralla, E.B., and Longo, V.D. (2003). SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163, 35-46. Fabrizio, P., Pletcher, S.D., Minois, N., Vaupel, J.W., and Longo, V.D. (2004). Chronological aging-independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae. FEBS Lett 557, 136-142. Fabrizio, P., Pozza, F., Pletcher, S.D., Gendron, C.M., and Longo, V.D. (2001). Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288-290. Finkbeiner, S. (2000). CREB couples neurotrophin signals to survival messages. Neuron 25, 11-14. Firestein, R., Blander, G., Michan, S., Oberdoerffer, P., Ogino, S., Campbell, J., Bhimavarapu, A., Luikenhuis, S., de Cabo, R., Fuchs, C., Hahn, W.C., Guarente, L.P., and Sinclair, D.A. (2008). The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., and Tsai, L.H. (2007). Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178-182. |
