The Molecular Components of Estrogen Receptor Beta (ERβ) Signaling in Neuronal Sytems

<p>With increasing life expectancy, women are now living upwards of 50 years without circulating estrogens, therefore, it is essential to investigate how the brain is changed by estrogen deprivation and also how aging influences these changes. The Women's Health Initiative (WHI) study spurred rigorous debate regarding estrogen therapy for postmenopausal women due to dichotomous effects of estrogens in menopausal and post-menopausal women. Meta-analyses of the WHI study revealed that after circulating estrogens are depleted for many years re-exposure may cause aberrant, negative health effects, indicating that there is an age-related `switch' in estrogen signaling around menopause. These age-related effects of HT expose a gap in scientific knowledge as to how estrogen receptors, ER&alpha; and ER&beta; signal when the body is deprived of estrogen and under the natural context of aging. ER&beta; regulates a number of genes governing grievous symptoms menopausal symptoms such as anxiety, depression, and cognitive decline. Further, alternative splice variants derived from ER&beta; do not bind estrogens as well as ER&beta;1, and importantly, ER&beta; splice variants increase in the brain with age. I hypothesized that altered splice variant signaling contributes to a switch in estrogen signaling around the time of menopause. Herein, I demonstrate that human ER&beta; splice variants are constitutively active transcription factors, supporting my hypothesis. I also describe another contribution to ER&beta; functions in the brain resulting from age and E2-dependent changes in protein:protein interactions with ER&beta;. This dissertation reveals 1) the varied transcriptional effects of ER&beta; alternative splice variants, 2) identification of novel ER&beta; protein interaction partners, 3) how these interactions and the expression of these proteins change as a factor of age and 4) the effects of changes in these interactions on gene transcription which could be part of the switch in molecular signaling of estrogens at the time of menopause.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell Biology, Neurobiology and Anatomy

Year dc:date.available

2014

Author dc:creator

• Mott, Natasha

• Molecular and Cellular Neuroscience

Repository record dc:identifier

https://ecommons.luc.edu/luc_diss/906

OAI identifier oai:identifier

oai:ecommons.luc.edu:luc_diss-1905