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List of Figures
Figure 1. SIRT1 inhibitors increase oxidative stress resistance in neurons ..............25
Figure 2. Effect of SIRT1 inhibitors alone on neuronal viability .............................26
Figure 3. Effect of high doses of nicotinamide on neuronal viability when exposed to oxidative stress........................................................................................27
Figure 4. Inhibition of SIRT1 deacetylase increases oxidative stress resistance in neurons .................................................................................................29
Figure 5. Inhibiting SIRT1 deacetylase does not protect against certain forms of stress in neurons....................................................................................................30
Figure 6. Inhibiting SIRT1 deacetylase does not alter MnSOD or catalase expression in cultured neurons ..................................................................................31
Figure 7. SIRT1 deacetylase does not alter the activation of Akt, S6 kinase or CREB in cultured neurons ........................................................................................33
Figure 8. SIRT1 inhibitors decrease Ras/ERK1/2 activation in cultured neurons ......................................................................................................................35
Figure 9. Inhibition of SIRT1 deacetylase decreases ERK1/2 activation in cultured neurons and in vivo .....................................................................................36
Figure 10. SIRT1 inhibitor decreases IGF-I-induced, but not PMA-induced ERK1/2 activation in HEK293 cells .........................................................................38
Figure 11. Subcellular localization of SIRT1 in hippocampus CA3 ........................40
Figure 12. Subcellular localization of SIRT1 in the forebrain ..................................41
Figure 13. Nucleus-cytosol shuttling of SIRT1 in cultured neurons ........................42
Figure 14. SIRT1 regulates Ras/ERK1/2 signaling via deacetylation of IRS-2 .......44
Figure 15. Representative blots showing the effect of SIRT1 on IRS-2 deacetylation in neurons ...........................................................................................45
Figure 16. Representative blots showing the effect of resveratrol on the acetylation level of IRS-2 .........................................................................................46
Figure 17. Inhibiting MEK/ERK1/2 protects neurons against oxidative stress ........48
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 6 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | vi List of Figures Figure 1. SIRT1 inhibitors increase oxidative stress resistance in neurons ..............25 Figure 2. Effect of SIRT1 inhibitors alone on neuronal viability .............................26 Figure 3. Effect of high doses of nicotinamide on neuronal viability when exposed to oxidative stress........................................................................................27 Figure 4. Inhibition of SIRT1 deacetylase increases oxidative stress resistance in neurons .................................................................................................29 Figure 5. Inhibiting SIRT1 deacetylase does not protect against certain forms of stress in neurons....................................................................................................30 Figure 6. Inhibiting SIRT1 deacetylase does not alter MnSOD or catalase expression in cultured neurons ..................................................................................31 Figure 7. SIRT1 deacetylase does not alter the activation of Akt, S6 kinase or CREB in cultured neurons ........................................................................................33 Figure 8. SIRT1 inhibitors decrease Ras/ERK1/2 activation in cultured neurons ......................................................................................................................35 Figure 9. Inhibition of SIRT1 deacetylase decreases ERK1/2 activation in cultured neurons and in vivo .....................................................................................36 Figure 10. SIRT1 inhibitor decreases IGF-I-induced, but not PMA-induced ERK1/2 activation in HEK293 cells .........................................................................38 Figure 11. Subcellular localization of SIRT1 in hippocampus CA3 ........................40 Figure 12. Subcellular localization of SIRT1 in the forebrain ..................................41 Figure 13. Nucleus-cytosol shuttling of SIRT1 in cultured neurons ........................42 Figure 14. SIRT1 regulates Ras/ERK1/2 signaling via deacetylation of IRS-2 .......44 Figure 15. Representative blots showing the effect of SIRT1 on IRS-2 deacetylation in neurons ...........................................................................................45 Figure 16. Representative blots showing the effect of resveratrol on the acetylation level of IRS-2 .........................................................................................46 Figure 17. Inhibiting MEK/ERK1/2 protects neurons against oxidative stress ........48 |
