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Acknowledgements
My gratitude goes to my family and friends whose love and support over the years have lit up my way in this foreign land distant from my home country. My advisor, Dr. Valter D. Longo, has consistently inspired, supported and supervised me throughout my academic quest and none of the work would have been possible without his insights. His influence of having big ideas, thinking out of the box and believing in self will continue to benefit me in the years to come. I am greatly obliged to Dr. Michel Baudry for tremendous advice and help in both of my research projects. Dr. Christian Pike has persistently encouraged and helped me throughout my graduate study. Dr. Stephen Madigan has provided me with valuable advice. I am also indebted to the past and present members in the Finch, Baudry, Pike and Davies laboratories for all the technical and intellectual help bestowed upon me. Drs. Min Wei, Paola Fabrizio, Federica Madia and Edoardo Parrella in Longo laboratory have given me vast support and guidance over the years. The warmth and assistance offered by my colleagues Jia Hu, Sangeeta Cook, Stavros Gonidakis, Abdoulaye Galbani, Priya Balasubramanian and Changhan Lee have made each day a memorable one.
The experiments in chapter 2 were also made possible by the work of Dr. Wei Xu and Dr. Michael McBurney. The experiments in chapter 3 were also a result of collaborative efforts from the laboratories of Dr. Michel Baudry, Dr. Rafael de Cabo and Dr. David A.
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 2 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | ii Acknowledgements My gratitude goes to my family and friends whose love and support over the years have lit up my way in this foreign land distant from my home country. My advisor, Dr. Valter D. Longo, has consistently inspired, supported and supervised me throughout my academic quest and none of the work would have been possible without his insights. His influence of having big ideas, thinking out of the box and believing in self will continue to benefit me in the years to come. I am greatly obliged to Dr. Michel Baudry for tremendous advice and help in both of my research projects. Dr. Christian Pike has persistently encouraged and helped me throughout my graduate study. Dr. Stephen Madigan has provided me with valuable advice. I am also indebted to the past and present members in the Finch, Baudry, Pike and Davies laboratories for all the technical and intellectual help bestowed upon me. Drs. Min Wei, Paola Fabrizio, Federica Madia and Edoardo Parrella in Longo laboratory have given me vast support and guidance over the years. The warmth and assistance offered by my colleagues Jia Hu, Sangeeta Cook, Stavros Gonidakis, Abdoulaye Galbani, Priya Balasubramanian and Changhan Lee have made each day a memorable one. The experiments in chapter 2 were also made possible by the work of Dr. Wei Xu and Dr. Michael McBurney. The experiments in chapter 3 were also a result of collaborative efforts from the laboratories of Dr. Michel Baudry, Dr. Rafael de Cabo and Dr. David A. |
