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ESTRADIOL REGULATION OF CEREBRAL METABOLISM: IMPLICATIONS FOR NEUROPROTECTION AND MITOCHONDRIAL BIOENERGETICS
by
Ronald W. Irwin
____________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
August 2008
Copyright 2008 Ronald W. Irwin
Object Description
| Title | Estradiol regulation of cerebral metabolism: implications for neuroprotection and mitochondrial bioenergetics |
| Author | Irwin, Ronald W. |
| Author email | ronaldir@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2008-03-24 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-06-02 |
| Advisor (committee chair) | Brinton, Roberta Diaz |
| Advisor (committee member) |
Baudry, Michel Cadenas, Enrique |
| Abstract | Herein are a collection of studies that build on our existing knowledge of estrogen actions in the brain. We extend the efforts of current neuroprotective strategies by demonstrating that estrogenic molecules promote cell survival mechanisms governed by neuronal mitochondria. Estrogen (E2, 17beta-estradiol) protects neurons from a series of age-related risk factors for developing Alzheimer 's disease (AD) supported by basic science, clinical, and epidemiological data. However, there exists a window of opportunity for E2 as a preventive therapy and our findings are not intended for hopeful treatments of pre-existing pathologies but rather to support the proposed healthy-cell bias therapeutic approach (Brinton 2005). Our preclinical pharmacology research work covers biochemistry, molecular biology and cell imaging of rodent brain. Controlled in vitro and in vivo studies are organized under four specific aims that test our hypotheses in brain tissues with a focus on the hippocampus and cortex regions involved in learning and memory and adversely affected in age-related dementias. Specific Aim 1 serves to determine the presence of estrogen receptors in mitochondria and the effects of E2 on the brain mitochondrial proteome. Specific Aim 2 focuses on E2 and P4 actions on the mitochondria and the mechanistic role of these hormones on mitochondrial function. Specific Aim 3 extends these basic science discoveries to test selective estrogen receptor modulators. Specific Aim 4 introduces the triple-transgenic mouse model of Alzheimer 's disease as a tool to test hormone therapies and intervene in cases of mitochondrial dysfunction. We believe that our experimental approach and subsequent findings will forge the way for a new class of E2-based mitochondrial therapeutics to reduce the risk of Alzheimer 's disease and other diseases attributed to mitochondrial malfunction. |
| Keyword | Estradiol; mitochondria; Alzheimer's disease; proteomics |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m1252 |
| Rights | Irwin, Ronald W. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Irwin-20080602 |
| Archival file | uscthesesreloadpub_Volume26/etd-Irwin-20080602.pdf |
Description
| Title | Page 1 |
| Full text | ESTRADIOL REGULATION OF CEREBRAL METABOLISM: IMPLICATIONS FOR NEUROPROTECTION AND MITOCHONDRIAL BIOENERGETICS by Ronald W. Irwin ____________________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) August 2008 Copyright 2008 Ronald W. Irwin |
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