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Estrogen Receptor Beta-Targeted Treatment to Maintain Cognitive Function During Menopause

雌激素受体β靶向治疗以维持更年期认知功能

基本信息

批准号：
9377473
负责人：
Laura Kammel
金额：
$ 3.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2018-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9377473
关键词：
Adult Age Aging Alzheimer&apos s Disease Andropause Behavioral Breast Cells Chronic Clinical Clinical Trials Cognitive Decision Making Disease Dose Electrophysiology (science)Estriol Estrogen Receptor alpha Estrogen Receptor beta Estrogens Etiology Female Formulation Gene Expression Genes Goals Gonadal Steroid Hormones Health Hippocampus (Brain)Hormone replacement therapy Hormone use Human Impaired cognition Knock-out Knockout Mice Mediating Mediator of activation protein Memory Menopausal Symptom Menopause Mission Modeling Molecular Target Mus National Institute on Aging Nerve Degeneration Neurologic Neurons Operative Surgical Procedures Outcome Measure Ovarian Ovariectomy Peripheral Population Predisposition Premature Menopause Production Proteins Quality of life Regulation Research Research Training Risk Rodent Slice Synapses Synaptic plasticity Synaptophysin Testosterone Therapeutic Tissues Woman Work World Health Organization age related aging hippocampus carcinogenicity cardiovascular disorder risk cell type cellular targeting clinically relevant cognitive function cost hormone therapy improved innovation male men middle age morris water maze neuropathology neuroprotection novel strategies older women postsynaptic density protein pre-clinical prevent protective effect public health relevance socioeconomics spatial memory synaptic function targeted treatment transcriptome treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Circulating sex hormones, particularly estrogens, provide neuroprotective effects in the hippocampus to promote synaptic plasticity and verbal/spatial memory throughout adulthood. For women, these effects are lost with the cessation of ovarian estrogen synthesis at menopause, compounding age-related hippocampal neurodegeneration and cognitive decline(6, 7). Furthermore, these neurological changes increase a woman's susceptibility to develop age-related disorders such as Alzheimer's disease (AD)(8, 9). No hormone therapy exists to maintain cognitive function during menopause. Only short-term use of hormone replacement therapy (HRT) is FDA recommended for the management of menopausal symptoms because estrogens in HRT can increase carcinogenic proliferation of breast and uterine tissue and increase cardiovascular disease risk in older women(21-26). These adverse health risks preclude current formulations of HRT from becoming a long- term treatment for preventing hippocampal decline following ovarian estrogen loss. While both estrogen receptors α and β (ERβ) have been associated with estrogen-mediated neuroprotection and memory following loss of ovarian estrogen, the ER-expressing cell-type mediating these functions is unknown, and the estrogen-regulated gene network has not been characterized at the cell-specific level. We have recently identified estriol, a clinically safe alternative to estrogens in HRT(23-26, 30, 31), as protective for hippocampal synaptic plasticity and spatial memory following loss of ovarian estrogen in a rodent ovariectomy (OVX) model. We hypothesize that estriol treatment is sufficient to maintain hippocampal plasticity and function following the loss of ovarian estrogen, and that these peripheral estrogen effects are mediated primarily by ERβ expressed on neurons through the regulation of synapse-associated, cytoskeletal, and survival genes. We will characterize estriol-mediated neuroprotection in the hippocampus using behavioral, electrophysiological, and neuropathological outcome measures in adult and middle-aged OVX mice. Furthermore, we will determine the cell-type and the ER responsible for mediating this effect using ER- conditional knockout mice generated in our lab. Finally, we will characterize the estrogen-sensitive transcriptome of hippocampal neurons in adult and middle-aged mice. This work is significant because it will evaluate a treatment with high clinical relevance specifically for cognitive decline during menopause, use innovative conditional knockout models to reveal the cellular and molecular targets of the protective effects of estrogen in the hippocampus, and identify gene expression changes in adult and middle-aged mice to help characterize the estrogen-sensitive gene network in hippocampal neurons occurring during both surgical/early menopause and natural menopause. It will also warrant clinical trials of estriol to prevent cognitive decline from menopause. Together, this proposal supports the National Institute on Aging mission to explore research questions that significantly contribute to informed decision-making for relieving menopausal symptoms.