: The overall goal of this research is to define the mechanisms and consequences of estrogens actions on the forebrain, which we will address in two specific aims.
The first aim i s to determine the cellular consequences of estrogen-mediated alterations in the ratio of neurotrophin receptors. In the adult forebrain, estrogen increases trk receptors and decreases p75, resulting in a favorable trk/p75 ratio, while in the reproductively senescent forebrain, estrogen replacement, paradoxically, results in an unfavorable trk/p75 ratio. While both neurotrophin receptors stimulate distinct and overlapping signaling pathways, the trks typically promote cell survival, while p75 may stimulate either cell survival or cell death. Here, our in vivo models will be used to assess how estrogen mediated changes in trk/p75 ratios will affect down-stream neurotrophin signaling and, consequently, cell fate, when challenged, in vivo, with neurotrophin stimulation or injury.
The second aim i s to test the hypothesis that expression/activation of the alpha form of the estrogen receptor (ER-alpha) is detrimental to cell health. Two estrogen receptors have been identified, although the specific contribution of each receptor to neural function is not clearly defined. Recent observations indicate that high ER-alpha expression is associated with decreased estrogen responsiveness on measures such as neurotrophin expression and cell survival. Estrogen receptor specific ligands, in conjunction with ex vivo and in vitro models, will be used to determine the contribution of each estrogen receptor to neurotrophin expression, signal transduction and cell death. These studies will also employ DNA microarray analysis, with the eventual goal of developing strategic gene arrays to facilitate rapid detection of estrogen-mediated cellular changes and to discriminate between the actions of receptor specific ligands. In view of the recent conflicting evidence regarding estrogen use and Alzheimer's disease, understanding the biology of estrogens actions are more critical now than ever. Moreover, identifying hormone-stimulated pathways that initiate cell-degenerative events will be increasingly important to the development of target and receptor specific estrogenic compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019515-03
Application #
6703650
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Monjan, Andrew A
Project Start
2002-02-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
3
Fiscal Year
2004
Total Cost
$260,308
Indirect Cost
Name
Texas A&M University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
141582986
City
College Station
State
TX
Country
United States
Zip Code
77845
Lewis, Danielle K; Bake, Shameena; Thomas, Kristen et al. (2010) A high cholesterol diet elevates hippocampal cytokine expression in an age and estrogen-dependent manner in female rats. J Neuroimmunol 223:31-8
Selvamani, Amutha; Sohrabji, Farida (2010) Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiol Aging 31:1618-28
Bake, Shameena; Ma, Lijiang; Sohrabji, Farida (2008) Estrogen receptor-alpha overexpression suppresses 17beta-estradiol-mediated vascular endothelial growth factor expression and activation of survival kinases. Endocrinology 149:3881-9
Lewis, Danielle K; Johnson, Adam B; Stohlgren, Shannon et al. (2008) Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female rats. J Neuroimmunol 195:47-59
Lewis, Danielle K; Woodin, Heather R; Sohrabji, Farida (2008) Astrocytes from acyclic female rats exhibit lowered capacity for neuronal differentiation. Aging Cell 7:836-49
Sohrabji, Farida (2007) Guarding the blood-brain barrier: a role for estrogen in the etiology of neurodegenerative disease. Gene Expr 13:311-9
Johnson, Adam B; Bake, Shameena; Lewis, Danielle K et al. (2006) Temporal expression of IL-1beta protein and mRNA in the brain after systemic LPS injection is affected by age and estrogen. J Neuroimmunol 174:82-91
Sohrabji, Farida; Lewis, Danielle K (2006) Estrogen-BDNF interactions: implications for neurodegenerative diseases. Front Neuroendocrinol 27:404-14
Sohrabji, Farida; Bake, Shameena (2006) Age-related changes in neuroprotection: is estrogen pro-inflammatory for the reproductive senescent brain? Endocrine 29:191-7
Johnson, Adam B; Sohrabji, Farida (2005) Estrogen's effects on central and circulating immune cells vary with reproductive age. Neurobiol Aging 26:1365-74

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