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Bordone, L., Motta, M.C., Picard, F., Robinson, A., Jhala, U.S., Apfeld, J., McDonagh, T., Lemieux, M., McBurney, M., Szilvasi, A., Easlon, E.J., Lin, S.J., and Guarente, L. (2006). SIRT1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4, e31.
Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., Hu, L.S., Cheng, H.L., Jedrychowski, M.P., Gygi, S.P., Sinclair, D.A., Alt, F.W., and Greenberg, M.E. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015.
Byron, S.A., Horwitz, K.B., Richer, J.K., Lange, C.A., Zhang, X., and Yee, D. (2006). Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. Br J Cancer 95, 1220-1228.
Cefalu, W.T., Bell-Farrow, A.D., Wang, Z.Q., Sonntag, W.E., Fu, M.X., Baynes, J.W., and Thorpe, S.R. (1995). Caloric restriction decreases age-dependent accumulation of the glycoxidation products, N epsilon-(carboxymethyl)lysine and pentosidine, in rat skin collagen. J Gerontol A Biol Sci Med Sci 50, B337-341.
Chakraborty, H., Sen, P., Sur, A., Chatterjee, U., and Chakrabarti, S. (2003). Age-related oxidative inactivation of Na+, K+-ATPase in rat brain crude synaptosomes. Exp Gerontol 38, 705-710.
Chen, C., and Tonegawa, S. (1997). Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annual Review of Neuroscience 20, 157-184.
Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.F., Kwon, H., Yi, S., Mucke, L., and Gan, L. (2005). SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 280, 40364-40374.
Cheng, C., Fabrizio, P., Ge, H., Longo, V.D., and Li, L.M. (2007). Inference of transcription modification in long-live yeast strains from their expression profiles. BMC Genomics 8, 219.
Cheung, E.C., and Slack, R.S. (2004). Emerging role for ERK as a key regulator of neuronal apoptosis. Sci STKE 2004, PE45.
Chu, C.T., Levinthal, D.J., Kulich, S.M., Chalovich, E.M., and DeFranco, D.B. (2004). Oxidative neuronal injury. The dark side of ERK1/2. Eur J Biochem 271, 2060-2066.
Chua, K.F., Mostoslavsky, R., Lombard, D.B., Pang, W.W., Saito, S., Franco, S., Kaushal, D., Cheng, H.L., Fischer, M.R., Stokes, N., Murphy, M.M., Appella, E., and
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 132 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 122 Bordone, L., Motta, M.C., Picard, F., Robinson, A., Jhala, U.S., Apfeld, J., McDonagh, T., Lemieux, M., McBurney, M., Szilvasi, A., Easlon, E.J., Lin, S.J., and Guarente, L. (2006). SIRT1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4, e31. Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., Hu, L.S., Cheng, H.L., Jedrychowski, M.P., Gygi, S.P., Sinclair, D.A., Alt, F.W., and Greenberg, M.E. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015. Byron, S.A., Horwitz, K.B., Richer, J.K., Lange, C.A., Zhang, X., and Yee, D. (2006). Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. Br J Cancer 95, 1220-1228. Cefalu, W.T., Bell-Farrow, A.D., Wang, Z.Q., Sonntag, W.E., Fu, M.X., Baynes, J.W., and Thorpe, S.R. (1995). Caloric restriction decreases age-dependent accumulation of the glycoxidation products, N epsilon-(carboxymethyl)lysine and pentosidine, in rat skin collagen. J Gerontol A Biol Sci Med Sci 50, B337-341. Chakraborty, H., Sen, P., Sur, A., Chatterjee, U., and Chakrabarti, S. (2003). Age-related oxidative inactivation of Na+, K+-ATPase in rat brain crude synaptosomes. Exp Gerontol 38, 705-710. Chen, C., and Tonegawa, S. (1997). Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annual Review of Neuroscience 20, 157-184. Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.F., Kwon, H., Yi, S., Mucke, L., and Gan, L. (2005). SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 280, 40364-40374. Cheng, C., Fabrizio, P., Ge, H., Longo, V.D., and Li, L.M. (2007). Inference of transcription modification in long-live yeast strains from their expression profiles. BMC Genomics 8, 219. Cheung, E.C., and Slack, R.S. (2004). Emerging role for ERK as a key regulator of neuronal apoptosis. Sci STKE 2004, PE45. Chu, C.T., Levinthal, D.J., Kulich, S.M., Chalovich, E.M., and DeFranco, D.B. (2004). Oxidative neuronal injury. The dark side of ERK1/2. Eur J Biochem 271, 2060-2066. Chua, K.F., Mostoslavsky, R., Lombard, D.B., Pang, W.W., Saito, S., Franco, S., Kaushal, D., Cheng, H.L., Fischer, M.R., Stokes, N., Murphy, M.M., Appella, E., and |
