Estrogen and cognition over the lifespan

雌激素与整个生命周期的认知

• 批准号: 8185299
• 负责人: THOMAS C FOSTER
• 金额: $ 29.42万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185299
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; American; Behavioral; Biological Assay; Biological Markers; Cognition; Data; Disease; Elderly; Estrogen Receptors; Estrogens; Etiology; Exhibits; Figs - dietary; Foundations; Gene Delivery; Gene Expression Profile; Genetic Polymorphism; Genetic Transcription; Genomics; Goals; Health; Hippocampus (Brain); Hormones; Impaired cognition; Incidence; Intervention; Knock-out; Knockout Mice; Longevity; Mediating; Memory; Memory impairment; Menopause; Modeling; Molecular; Mus; Neurodegenerative Disorders; Oils; Performance; Personal Satisfaction; Population; Prevalence; Public Health; Publishing; Rattus; Research; Risk; Role; Signal Transduction; Subfamily lentivirinae; Synapses; Techniques; Testing; Therapeutic; Vertebral column; Viral; Viral Vector; Water; Woman; Work; age effect; age related; aged; design; improved; innovation; knock-down; middle age; neuroprotection; novel strategies; prevent; programs; receptor; receptor expression; small hairpin RNA; synaptogenesis; therapy development; vector

DESCRIPTION (provided by applicant): The long range goal is intervention to delay or prevent cognitive decline associated with unsuccessful aging, in order to improve the health and well-being of older Americans. The incidence of Alzheimer's disease is projected to increase dramatically, with the greatest prevalence in women. Synaptic loss contributes to memory impairments and estrogen (E2) promotes synaptogenesis and memory. Thus, E2 treatment could have a major impact on public health. However, the efficacy of E2 is greatly reduced if therapy occurs several years after the onset of menopause, suggesting a temporally limited therapeutic window. Evidence indicates estrogen receptor (ER) expression and ER polymorphisms contribute to a variety of hormone sensitive diseases, including cognitive decline. We hypothesize that differential expression of ER1 and ER2 interacts with the level of E2 to contribute to 1) the etiology of age-related memory deficits, 2) loss of E2 mediated synaptogenesis, and 3) the closing of the E2 therapeutic window. Aim 1 will combine aging ER1 and ER2 knockout mice with viral vectors to influence ER expression and systematically perform behavioral, molecular, and electrophysiological assays to test the hypothesis. Aim 2 will employ hippocampal viral delivery vectors to increase or decrease ER1 or ER2 in young, middle-age, and aged rats, and will use behavioral and molecular assays to test the hypothesis that shifting the ratio of ER1/ER2 expression rejuvenates hippocampal function. Aim 3 will employ viral vectors to alter the expression of ER1 or ER2, and will test the hypothesis that ER expression contributes to age-related changes in rapid E2 signaling. Knockout mice and viral vector gene delivery provide novel approaches to test the hypothesis that ER expression is a contributing factor for hippocampal aging. Together, these studies will determine whether altering the level of ER1 or ER2 expression is important for age-related memory decline, E2-induced synaptogenesis, and closing of the E2 therapeutic window, and will provide the groundwork for development of therapies to slow or prevent cognitive decline associated with aging and age-related diseases. PUBLIC HEALTH RELEVANCE: Research to reduce cognitive decline is crucial, given the burgeoning number of elderly, in which 3 in 10 will display serious cognitive decline due to age and Alzheimer's disease. Women exhibit greater risk for cognitive decline and comprise greater than 60% of the Alzheimer population. These studies will provide a scientific foundation for interventions to avert the impending wave of cognitively impaired seniors.

描述（由申请人提供）：长期目标是进行干预，以延缓或预防与衰老失败相关的认知能力下降，以改善美国老年人的健康和福祉。阿尔茨海默病的发病率预计将急剧增加，其中女性患病率最高。突触丧失会导致记忆障碍，而雌激素 (E2) 会促进突触发生和记忆。因此，E2 治疗可能对公众健康产生重大影响。然而，如果在绝经开始几年后进行治疗，E2 的疗效会大大降低，这表明治疗窗口在时间上是有限的。有证据表明雌激素受体 (ER) 表达和 ER 多态性会导致多种激素敏感性疾病，包括认知能力下降。我们假设 ER1 和 ER2 的差异表达与 E2 水平相互作用，导致 1) 年龄相关记忆缺陷的病因，2) E2 介导的突触发生的丧失，以及 3) E2 治疗窗的关闭。目标 1 将衰老的 ER1 和 ER2 敲除小鼠与病毒载体结合起来，影响 ER 的表达，并系统地进行行为、分子和电生理学测定来检验这一假设。目标 2 将利用海马病毒递送载体来增加或减少年轻、中年和老年大鼠的 ER1 或 ER2，并将使用行为和分子测定来检验改变 ER1/ER2 表达比例可以恢复海马功能的假设。目标 3 将采用病毒载体来改变 ER1 或 ER2 的表达，并将检验 ER 表达有助于快速 E2 信号传导中与年龄相关的变化的假设。基因敲除小鼠和病毒载体基因递送提供了新的方法来检验 ER 表达是海马衰老的一个促成因素的假设。总之，这些研究将确定改变 ER1 或 ER2 表达水平对于与年龄相关的记忆衰退、E2 诱导的突触发生和 E2 治疗窗口的关闭是否重要，并将为开发减缓或预防的疗法奠定基础。与衰老和年龄相关疾病相关的认知能力下降。 公共健康相关性：考虑到老年人数量不断增加，减少认知能力下降的研究至关重要，其中十分之三的人会因年龄和阿尔茨海默病而出现严重的认知能力下降。女性认知能力下降的风险更大，占阿尔茨海默病人群的 60% 以上。这些研究将为干预措施提供科学基础，以避免即将出现的认知障碍老年人浪潮。