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

• 批准号: 9124519
• 负责人: Laura Kammel
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/9124519
• 关键词: Adult; Age; Aging; Alzheimer' 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; 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; Treatment Cost; Woman; Work; World Health Organization; age related; aging hippocampus; cardiovascular disorder risk; cell type; cellular targeting; clinically relevant; cognitive function; 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; transcriptome; treatment strategy

 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.

 描述（由申请人提供）：循环性激素，特别是雌激素，在海马体中提供神经保护作用，以促进整个成年期的突触可塑性和言语/空间记忆。对于女性，这些影响随着绝经期卵巢雌激素合成的停止而消失，加剧了年龄相关的海马神经变性和认知能力下降（6，7）。此外，这些神经系统的变化增加了妇女的易感性，发展与年龄有关的疾病，如阿尔茨海默病（AD）（8，9）。没有激素治疗存在维持认知功能在更年期。只有短期使用激素替代疗法（HRT）是FDA推荐的更年期症状的管理，因为激素替代疗法中的雌激素会增加乳腺和子宫组织的致癌性增殖，并增加老年妇女的心血管疾病风险（21-26）。这些不利的健康风险排除了目前的HRT制剂成为预防卵巢雌激素丢失后海马衰退的长期治疗。虽然雌激素受体α和β（ERβ）与卵巢雌激素丧失后雌激素介导的神经保护和记忆有关，但介导这些功能的ER表达细胞类型尚不清楚，雌激素调节的基因网络尚未在细胞特异性水平上表征。我们最近发现雌三醇是HRT中雌激素的一种临床安全替代品（23-26，30，31），在啮齿动物卵巢切除术（OVX）模型中卵巢雌激素丧失后，可保护海马突触可塑性和空间记忆。我们假设雌三醇治疗足以维持卵巢雌激素丧失后海马的可塑性和功能，并且这些外周雌激素效应主要由神经元上表达的ERβ通过调节突触相关基因、细胞骨架基因和存活基因介导。我们将在成年和中年OVX小鼠中使用行为，电生理和神经病理学结果测量来表征雌三醇介导的海马神经保护作用。此外，我们将使用我们实验室中产生的ER条件性敲除小鼠来确定负责介导这种效应的细胞类型和ER。最后，我们将描述成年和中年小鼠海马神经元的雌激素敏感性转录组。这项工作意义重大，因为它将评估一种具有高度临床相关性的治疗方法，特别是针对绝经期认知能力下降的治疗方法，使用创新的条件性敲除模型来揭示海马中雌激素保护作用的细胞和分子靶点，并确定成年和中年小鼠的基因表达变化，以帮助描述在手术/手术期间海马神经元中发生的雌激素敏感基因网络。早期绝经和自然绝经。这也将保证雌三醇的临床试验，以防止更年期认知能力下降。总之，这项建议支持国家老龄化研究所的使命，探索研究问题，大大有助于明智的决策，以缓解更年期症状。