The discrepancy between numerous basic science, epidemiological and clinical studies that supported thepotential benefit of hormone therapy in preventing age-associated cognitive impairment, and the recentlypublished results from the Women's Health Initiative Memory Study (WHIMS), underscores the fact that ourunderstanding of hormone neurobiology is incomplete. Since the mechanisms of gonadal steroid hormonesin reproductive tissue may not be identical to that of the brain, a better understanding of how thesehormones work in the brain is needed. To this end, we will systematically address the role of the newlydiscovered membrane progesterone receptor (mPR) in mediating the neuroprotective effects ofprogesterone. Further, we propose that the failure of the WHIMS to show positive effects of hormone therapywas due, in part, to the synthetic progestin used in the hormone therapy regimen, medroxyprogesteroneacetate (MPA), and hypothesize that its lack of efficacy is due to important differences in its mechanism ofaction, relative to that of progesterone. Our hypotheses will be tested in primary cortical cultures (explantsand dissociated neurons) in which we have confirmed the expression of the classical progesterone receptor(PR) and the mPR as well. We will use complementary pharmacological (cell membrane impermeableprogestins), molecular (siRNA) and genetic tools (PRKO mice) to address the following aims:
Aim 1 :deterimine if the mPR mediates the effects of progesterone on the ERK/MAPK pathway (a pathway that weshow is required for progesterone-induced protection);
Aim 2 : determine if PR-specific patterns of ERKphosphorylation may explain the difference between progesterone's and MPA's ability to protect;
Aim 3 :determine if the mPR mediates the effect of progesterone on cell survival;
and Aim 4 : determine ifprogesterone protects in an in vivo model of stroke, specifically, in animals whose expression of the classicalPR has been disrupted (PRKO). The ovariectomized, 'stroked' mouse will serve as a common model usedby all projects within this Program of research and will enhance and facilitate the conceptual andexperimental integration among projects. Collectively, the studies proposed in this project may identify themPR as an important molecule to which future drug discovery efforts can target for the treatment orprevention of brain dysfunction resulting from age- or age-associated diseases like Alzheimer's Disease.
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