The long-term goal of our research program is to develop an estrogen replacement therapy that meets the unique requirements of the brain by activating estrogen-inducible mechanisms of memory and neuroprotection without activating mechanisms of proliferation within the uterus or breast. To achieve this long-term goal, multiple levels of mechanistic understanding of estrogen receptor function in brain must first be achieved. Towards elucidating mechanisms of estrogen promoted neuroprotection, we propose a model of estrogen-inducible proactive adaptation as a strategy whereby estrogen proactively protects neurons against insults of calcium dysregulation. The proposed model incorporates both novel mitochondria mechanisms of estrogen action and several existing estrogen-inducible pathways into a unified concept of proactive adaptation.
Four specific aims are proposed.
Specific Aim 1 will determine essential basics and generalizability of 17beta-estradiol (E2)-induced mitochondrial sequestration of calcium.
Specific Aim 2 will investigate the impact of 17beta-estradiol on the threshold for mitochondrial Ca 2+ sequestration and the underlying mechanism for the shift in threshold.
Specific Aim 3 will address the mechanism by which 17beta-estradiol protects against increased mitochondrial calcium load to prevent mitochondrial dysfunction.
Specific Aim 4 will determine the mechanism underlying 17beta-estradiol regulation of Bcl-2 family of proteins. Throughout each of the specific aims, we will determine whether 17beta-estradiol-induced mitochondria mechanisms activated in vitro are present in vivo. Seven technological approaches will be extensively utilized: neuronal culture, fluorescent intracellular calcium imaging, biochemical analyses of enzyme activation, immunocytochemical protein labeling, Western blot, mitochondrial isolation and HPLC for polyamines. Mitochondrial function will be assessed within cultured hippocampal neurons and in mitochondria derived from adult rat hippocampal neurons. Results of the proposed studies will provide a unified mechanistic model of estrogen-induced neuroprotection that incorporates both novel mitochondria mechanisms of estrogen action and estrogen-inducible MAPK, AKT and antiapoptotic pathways. From a clinical perspective, elucidation of the sites and targets of estrogen action should have a clear impact on both the use of estrogen replacement therapy for the prevention of neurodegenerative disease and the future design of target specific estrogens. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067159-05
Application #
7228200
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Desmond, Nancy L
Project Start
2003-06-01
Project End
2009-04-30
Budget Start
2007-05-24
Budget End
2009-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$254,231
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Irwin, R W; Yao, J; To, J et al. (2012) Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function. J Neuroendocrinol 24:236-48
Wu, Tzu-Wei; Chen, Shuhua; Brinton, Roberta D (2011) Membrane estrogen receptors mediate calcium signaling and MAP kinase activation in individual hippocampal neurons. Brain Res 1379:34-43
Zhao, Liqin; Yao, Jia; Mao, Zisu et al. (2011) 17?-Estradiol regulates insulin-degrading enzyme expression via an ER?/PI3-K pathway in hippocampus: relevance to Alzheimer's prevention. Neurobiol Aging 32:1949-63
Rettberg, Jamaica R; Hamilton, Ryan T; Mao, Zisu et al. (2011) The effect of dietary soy isoflavones before and after ovariectomy on hippocampal protein markers of mitochondrial bioenergetics and antioxidant activity in female monkeys. Brain Res 1379:23-33
Brinton, Roberta Diaz (2009) Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci 30:212-22
Yao, Jia; Irwin, Ronald W; Zhao, Liqin et al. (2009) Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 106:14670-5
Brinton, Roberta Diaz (2008) The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci 31:529-37
Brinton, Roberta Diaz (2008) Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease. Adv Drug Deliv Rev 60:1504-11
Irwin, Ronald W; Yao, Jia; Hamilton, Ryan T et al. (2008) Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. Endocrinology 149:3167-75
Nilsen, Jon; Irwin, Ronald W; Gallaher, Timothy K et al. (2007) Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci 27:14069-77

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