Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology, Molecular Biology and Biochemistry

Abstract

Hormone Therapy (HT) is used to increase the 17β-estradiol (E2) levels in women who are going through the menopausal transition to alleviate the negative symptoms associated with menopause and decrease the risk of chronic diseases. Clinical and basic science research had previously shown that HT provided protection from cognitive decline and reduced the risk of dementia. However the Women's Health Initiative (WHI) clinical trial demonstrated that HT had no beneficial effects for cognitive decline and, in some cases increased the risk of dementia in post-menopausal women. However, further analysis of WHI data showed that when HT was given to women who were just starting menopause, they experienced beneficial effects including a decreased risk for cognitive decline and a reduced risk of dementia. The results suggested that there was a "critical window" for the treatment of menopausal women, past which HT would not be effective. The molecular mechanisms underlying this critical period are currently not known. This dissertation attempts to understand how regulation of novel non-coding RNAs, called microRNAs, maybe responsible for the lost effectiveness of HT.

Knowledge of the molecular actions of estrogen in the brain is required to develop novel therapies for post-menopausal women and provide a foundation for understanding the clinical results of hormone therapy. The results of this dissertation provide evidence of the direct regulation of miRNAs by E2 in the brain and identify a set of miRNAs that are regulated in an age-dependent manner. These data suggest that miRNAs could be a mechanistic explanation for the observed altered efficacy of HT in post-menopausal women.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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