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synaptic glutamate receptors. Along the same lines, the signaling pathways through which SIRT1 may regulate synaptic plasticity remains to be identified. SIRT1 has been shown to modulate insulin/IGF-I signaling as well as endothelial nitric oxide synthase (eNOS) signaling, both of which are involved in synaptic plasticity. Inhibiting or activating these signaling pathways may uncover the roles of these transductions on SIRT1-mediated modulation of synaptic plasticity. In addition, analysis of microarray data from wild type, SIRT1 overexpressing and SIRT1 deficient mice may yield certain genes involved in learning and memory whose expression is regulated by SIRT1. It is very likely that several different mechanisms may together explain the effect of SIRT1 on learning and memory and that SIRT1 modulates synaptic plasticity with different mechanisms in different brain regions. Therefore, it is not unlikely to observe differential performance in different memory tasks.
Together, my parts of research indicate that SIRT1 can be both pro- and anti- aging and it plays multifaceted functions in aging and normal brain function.
Apart from the above important scientific implications, our results on the connection between SIRT1 and neuronal oxidative damage and the relationship between SIRT1 and learning and memory are of practical significance too, especially due to the fervid pursuit of sirtuins as potential anti-aging drug targets. The initial studies showed that Sir2 extended longevity in several lower organisms and suggested Sir2 as a key mediator of the life span extension from calorie restriction. Adding to the excitement is the
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 128 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 118 synaptic glutamate receptors. Along the same lines, the signaling pathways through which SIRT1 may regulate synaptic plasticity remains to be identified. SIRT1 has been shown to modulate insulin/IGF-I signaling as well as endothelial nitric oxide synthase (eNOS) signaling, both of which are involved in synaptic plasticity. Inhibiting or activating these signaling pathways may uncover the roles of these transductions on SIRT1-mediated modulation of synaptic plasticity. In addition, analysis of microarray data from wild type, SIRT1 overexpressing and SIRT1 deficient mice may yield certain genes involved in learning and memory whose expression is regulated by SIRT1. It is very likely that several different mechanisms may together explain the effect of SIRT1 on learning and memory and that SIRT1 modulates synaptic plasticity with different mechanisms in different brain regions. Therefore, it is not unlikely to observe differential performance in different memory tasks. Together, my parts of research indicate that SIRT1 can be both pro- and anti- aging and it plays multifaceted functions in aging and normal brain function. Apart from the above important scientific implications, our results on the connection between SIRT1 and neuronal oxidative damage and the relationship between SIRT1 and learning and memory are of practical significance too, especially due to the fervid pursuit of sirtuins as potential anti-aging drug targets. The initial studies showed that Sir2 extended longevity in several lower organisms and suggested Sir2 as a key mediator of the life span extension from calorie restriction. Adding to the excitement is the |
