The goal of this application is to determine the mechanisms by which reproductive aging and estrogen replacement alter the inflammatory response and consequently the neuronal environment. In a series of studies, we have established that estrogen replacement to young adult animals increases trophic support in the forebrain and attenuates inflammation following neural injury. However estrogen replacement at reproductive senescence, which is physiologically akin to menopause, fails to increase trophic factors and paradoxically, increases inflammatory mediators following neural injury. Collectively these data suggest that the timing of estrogen replacement in relation to reproductive aging may critically determine whether estrogen has a benign or deleterious outcome. Our central hypothesis is that the age-related decline in endogenous hormones triggers compensatory changes in estrogen receptor systems in specific immune cells, thus increasing the central and peripheral inflammatory response. This hypothesis will be tested in three Specific Aims, using animal and human tissue models that span the reproductive spectrum, namely, normally cycling (pre-menopause). irregularly cycling (perimenopause) and reproductive senescent (postmenopause).
In Specific Aim 1. we will test the hypothesis that permissive changes in the blood brain barrier will cause a more rapid and robust neural inflammation in reproductive senescent animals as compared to normally cycling or irregularly cycling animals. Animals will be injected systemically with the bacterial pathogen lipopolysaccharide (LPS) and inflammatory mediators will be measured in peripheral organs and the brain. Additionally, we will examine endothelial cells of the blood-brain barrier for reproductive age-related changes in this barrier.
In Specific Aim 2. we will determine if the inflammatory response of peripheral blood mononuclear cells (PBMC) is affected by clinically-relevant variables namely, the route of hormone administration (oral versus transdermal) and diet (regular versus high cholesterol). The Response Quotient, derived from an ex vivo LPS challenge assay, will be measured in rat and human blood samples to determine if salient lifestyle variables increase the risks associated with reproductive aging. Finally, in Specific Aim 3 we will test the hypothesis that compensatory alterations of the estrogen receptor system, resulting from ovarian decline, is a principal mechanism underlying estrogen's deleterious effects in reproductive senescence. Changes in the pattern and levels of estrogen receptor (ER)-alpha will be evaluated by immunohistochemistry and Western blots, while functional changes will be evaluated using signaling arrays. Human and rodent PBMC's and rodent cerebral endothelial cells from each reproductive stage will be studied. Collectively, these studies will test the hypothesis that in order for estrogen replacement to be beneficial, therapy must be initiated before compensatory responses to ovarian decline.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027684-04
Application #
7617675
Study Section
Special Emphasis Panel (ZRG1-EMNR-J (50))
Program Officer
Fuldner, Rebecca A
Project Start
2006-05-15
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$198,683
Indirect Cost
Name
Texas A&M University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Sohrabji, Farida; Bake, Shameena; Lewis, Danielle K (2013) Age-related changes in brain support cells: Implications for stroke severity. Neurochem Int 63:291-301
Sohrabji, Farida; Selvamani, Amutha; Balden, Robyn (2013) Revisiting the timing hypothesis: biomarkers that define the therapeutic window of estrogen for stroke. Horm Behav 63:222-30
Sohrabji, F; Williams, M (2013) Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia. J Neuroendocrinol 25:1173-81
Balden, Robyn; Selvamani, Amutha; Sohrabji, Farida (2012) Vitamin D deficiency exacerbates experimental stroke injury and dysregulates ischemia-induced inflammation in adult rats. Endocrinology 153:2420-35
Lewis, Danielle K; Thomas, Kristen T; Selvamani, Amutha et al. (2012) Age-related severity of focal ischemia in female rats is associated with impaired astrocyte function. Neurobiol Aging 33:1123.e1-16
Selvamani, Amutha; Sathyan, Pratheesh; Miranda, Rajesh C et al. (2012) An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS One 7:e32662
Selvamani, Amutha; Sohrabji, Farida (2010) The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. J Neurosci 30:6852-61
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; Friedman, Jonathan A; Sohrabji, Farida (2009) Reproductive age-related changes in the blood brain barrier: expression of IgG and tight junction proteins. Microvasc Res 78:413-24

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