Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Female life expectancy in the United States has steadily increased and now averages 81 years. Meanwhile, the age at which women reach menopause remains constant at 51 years. Both neurological and cardiovascular disorders increase following menopause, affecting women’s quality of life and leading to large health care costs. Estrogens are neuroprotective and cardioprotective for women, however when administered long after menopause, they fail to improve their health.

The effects of estrogen are mediated by Estrogen Receptor α (ERα) and Estrogen Receptor β (ERβ). Evidence supports that ERβ plays an important role in neuroprotection and cardioprotection, but aspects of ERβ molecular signaling are still not fully understood. One possibility is that aging and estrogen deprivation alter ERβ post translational modifications, such as phosphorylation. Indeed the mitogen activated protein kinases (MAPKs) responsible for phosphorylation of ERβ are modulated by aging and steroid hormones. Therefore, I hypothesized that MAPKs are sensitive to menopause leading to a differential phosphorylation of ERβ which results in altered transcriptional regulation.

First, phosphorylated ERβ was detected in the heart and brain of aged female rats prompting further investigation on functional consequences of this modification. Phosphorylation of ERβ was found to alter both its ligand dependent and ligand independent regulation of transcription. Therefore, ERβ phosphorylation would lead to differential gene regulation both in absence of estrogen or following estrogen treatment.

Using an animal model of menopause in aged female rats, we found that the expression and activation of the MAPKs that phosphorylate ERβ are sensitive to estrogen deprivation and treatment in the brain and heart. Altered kinase activity could have important physiological consequences as they control many cell signaling required for cell function. Furthermore altered kinase activation could result in differential ERβ phosphorylation and downstream effects on gene regulation. To detect and measure phosphorylated ERβ in vivo I designed a targeted mass spectrometry method that has been successful for the detection of lowly expressed proteins.

Taken together, the data presented in my dissertation demonstrate that alternative regulation of MAPKs signaling in the brain and heart could provide a novel mechanism explaining the variable effects of estrogen treatment following menopause.

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