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that in wild type (4.5 ± 0.2 nmol/mg; P < 0.05, n=7, t-test). This reduction of markers of oxidative stress in SIRT1 knockout mouse brain is consistent with our findings in culture. Although a recent report determined that SIRT1 protects the heart against oxidative stress (Alcendor et al., 2007a) these results suggest that SIRT1 may play a different role in the brain and other cells.
Figure 20. Reduced oxidative damage in SIRT1 knockout mouse brain
Protein carbonyl content (A) and lipid peroxidation (B) were measured in 18 month old SIRT1 +/+ and -/- mice brains. Protein carbonyl was measured with OxiSelect™ Protein Carbonyl ELISA Kit and data are shown as nmol protein carbonyl per mg of protein (*P < 0.05, n=7, t-test). Lipid peroxidation was measured using TBARS assay and data are presented as nmol malondialdehyde (MDA) equivalent per mg of protein (*P < 0.05, n=7, t-test). Data are represented as mean±SEM.
The reduced oxidative damage in SIRT1 knockout mouse brain confirmed our findings in culture that inhibition of SIRT1 increased stress resistance in neurons. However, other groups have also shown that SIRT1 is beneficial in other organs, such as the heart (Alcendor et al., 2007a). Considering the diverse roles SIRT1 play in different organs it is important to assess its effect on overall stress resistance. Thus, we tested the effect of SIRT1 inhibitor nicotinamide in response to exogenously induced oxidative stress. 2-month old male C57BL/6J mice were intraperitoneally (i.p.) injected either nicotinamide (500 mg per kg body mass) (n=12) or 0.09% saline (n=12) as control twice daily for 7
51
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 61 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | that in wild type (4.5 ± 0.2 nmol/mg; P < 0.05, n=7, t-test). This reduction of markers of oxidative stress in SIRT1 knockout mouse brain is consistent with our findings in culture. Although a recent report determined that SIRT1 protects the heart against oxidative stress (Alcendor et al., 2007a) these results suggest that SIRT1 may play a different role in the brain and other cells. Figure 20. Reduced oxidative damage in SIRT1 knockout mouse brain Protein carbonyl content (A) and lipid peroxidation (B) were measured in 18 month old SIRT1 +/+ and -/- mice brains. Protein carbonyl was measured with OxiSelect™ Protein Carbonyl ELISA Kit and data are shown as nmol protein carbonyl per mg of protein (*P < 0.05, n=7, t-test). Lipid peroxidation was measured using TBARS assay and data are presented as nmol malondialdehyde (MDA) equivalent per mg of protein (*P < 0.05, n=7, t-test). Data are represented as mean±SEM. The reduced oxidative damage in SIRT1 knockout mouse brain confirmed our findings in culture that inhibition of SIRT1 increased stress resistance in neurons. However, other groups have also shown that SIRT1 is beneficial in other organs, such as the heart (Alcendor et al., 2007a). Considering the diverse roles SIRT1 play in different organs it is important to assess its effect on overall stress resistance. Thus, we tested the effect of SIRT1 inhibitor nicotinamide in response to exogenously induced oxidative stress. 2-month old male C57BL/6J mice were intraperitoneally (i.p.) injected either nicotinamide (500 mg per kg body mass) (n=12) or 0.09% saline (n=12) as control twice daily for 7 51 |
