UNDERGRADUATE SUMMER RESEARCH PROGRAM
2010 NSSP Information
Jun Ming Wang
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Small Grant Principal Investigator Assistant Professor of Pathology Adj. Assistant Professor of Psychiatry Adj. Assistant Professor of Pharmacoloy & Toxicology University of Mississippi Medical Center Jackson, Mississippi 39216 Contact Dr. Wang Publications Key Research Personnel: Elise Gomez-Sanchez, DVM, Ph.D., Basic Science Mentor Mark C. Austin, Ph.D., Consultant Cynthia Bethea, Ph.D., Consultant Ian A. Paul, Ph.D., Consultant Craig A. Stockmeier, Ph.D., Consultant Laboratory Personnel: Zhi He, Instructor Roseanne Hill, Researcher II |
SMALL GRANT 2
ESTROGEN RECEPTOR SPLICE
VARIANTS
AND MENOPAUSE RELATED DEPRESSION
Several rigorous, standardized psychiatric diagnoses studies conclude that vulnerability to a major depressive disorder (MDD) is increased at the time of the menopause transition. About 75% of perimenopausal women reported mood and sleep disorders and these disorders are likely to recur at menopause in women with bipolar illness (Parry, 2008). The MDD may result in significant morbidity due to suicide and increased risk for a number of diseases including cancer, cardiovascular disease and stroke. Most of today's women live 25 to 30 years, one third of their lives, after menopause. Estrogen replacement therapy resulted in significant (more than 80%) anti-depressive effects in pre-, perimenopausal women but has no effects in late post-menopausal women.
From a public health point of view, research into the etiology of menopausal MDD and the development of effective therapeutic strategies will alleviate the emotional and financial burden on patients and their families, thereby improving their overall health and quality of life, and will significantly reduce the public healthcare burden resulting from untreated or poorly managed perimenopausal/menopausal MDD.
The functional, structural and/or mechanistic alterations of estrogen response during menopausal transition remains unclear and elucidating the nature of the loss of response to exogenous estrogen in late post-menopausal women forms the objective of this proposal. We and other groups have recently identified several estrogen receptor (ER) splice variants including the dominant negative ERbeta variant, ERbeta2 in rat hippocampus. Furthermore, our pilot data demonstrate an increase of ERbeta2 expression in hippocampus of rats ovariectomized (OVX) more than 21 days, but not in those OVX for 5 days or non OVX. Coincident with the increase of ERbeta2 expression in hippocampus of 21 days OVX rats is the loss of estrogen-induced neurogenesis which currently believe is a neural basis for antidepressants.
Therefore, we hypothesize that menopausal related ERbeta2 expression may serve as a biomarker and perhaps also as a functional switch for the menopause-related loss of estrogen antidepressive effects. Three specific AIMs are designed to validate our hypothesis: 1) characterize the ovariectomy-induced ER_2 isoform expression in the brains of rats and rhesus monkeys; (2) determine the impact of ER_2 on E2-regulated brain antidepressant effects in the brains OVX rats and non-human primates; (3) determine the impact of ER_2 on E2-regulated behavioral antidepressant effects in OVX rats.