Phyllis Wise

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Studies to assess estradiol's ability to protect the brain against injury and neurodegenerative diseases.

Recent studies suggest that estrogen therapy in postmenopausal women influences memory and cognitive dysfunction, the incidence and progression of brain injury associated with diseases such as Alzheimer's, and the recovery from stroke and other forms of brain injury. The unexpected results of the Women's Health Initiative make it even more important to determine what kinds of hormone therapy afford protection versus increase risk. If estrogens are important in maintaining normal brain function, then the menopause and resulting hypoestrogenicity may have deleterious repercussions on neural function during aging. We have discovered that low physiological levels of estradiol profoundly protect the brain against stroke injury. Our long-term objectives are to understand the underlying mechanisms that mediate estrogen's protective actions. We wish to decipher how estradiol enhances the survival and repair of injured neurons and the birth and proliferation of new neurons in the adult brain. Studies are underway to test the hypothesis that estradiol acts on the adult and aging brain to maintain neuronal structure and function by influencing cell death and/or neurogenesis. We are exploring whether these effects are mediated through actions on (1) trophic factors and their receptors, (2) structural genes that enhance plasticity and synaptogenesis, (3) the immune system and/or (4) oxidative stress. We are evaluating whether estradiol's effects are mediated by the estrogen receptor and whether they involve cross-talk with other second messenger systems. We are assessing the trophic and protective effects of estradiol in both in vivo and in vitro models.

The role of the brain in reproductive aging.

The brain clearly plays a critical role in the transition to age-related infertility. We have discovered that during middle age (1) estradiol's ability to modulate the rhythmic neurochemical events that are required for preovulatory GnRH/LH surges diminishes and (2) during this transitional period, changes in the ability of the suprachiasmatic nucleus (SCN), the major circadian pacemaker in mammals, to drive diurnal neurochemical events lead to declining precision in the timing of the GnRH/LH surge. Our long-term objectives are to understand the neural, cellular and molecular mechanisms by which estradiol and the circadian pacemaker interact to yield cyclic GnRH neuronal activity that leads to LH surges at the proper time and of the proper amplitude and how these mechanisms change with age. In ongoing studies, we are (1) assessing whether the diurnal patterns of expression of key neuromodulators that are heavily expressed in specific regions of the brain or their ability to communicate with GnRH neurons are attenuated with age; (2) evaluating whether these changes result from attenuated responsiveness to estradiol; (3) determining whether age-related changes in responsiveness to estradiol result from changes in the receptor (ERalpha or ERbeta), the ability of estrogen receptors to cross-talk with second messenger signaling systems and/or changes in co-regulator interactions with estrogen receptors and (4) evaluating whether lifelong exposure to cyclic estrogen secretion masculinizes sexually dimorphic regions of the female brain and makes it incapable of cyclic hormone secretion.

We are using in situ hybridization, real time-PCR, immunocytochemistry and DNA and protein array technology to monitor changes in the level of mRNA and protein. We have implemented Western analysis, ELISA and radioimmunoassay methods to quantify protein levels. We are using methods that involve the use of whole animals and in vitro dispersed neuron and astrocyte culture methods to approach these questions.


Selected Relevant Publications