Estrogen and cognition over the lifespan

雌激素与整个生命周期的认知

• 批准号: 8318597
• 负责人: THOMAS C FOSTER
• 金额: $ 29.33万
• 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/8318597
• 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.

描述（由申请人提供）：远距离目标是干预措施，以延迟或预防与不成功衰老有关的认知下降，以改善老年人的健康和福祉。阿尔茨海默氏病的发病率预计将大大增加，而女性的患病率最高。突触损失导致记忆障碍，雌激素（E2）促进突触发生和记忆。因此，E2治疗可能会对公共卫生产生重大影响。但是，如果治疗发生在更年期开始几年后，则E2的功效大大降低，这表明治疗窗口有限。证据表明雌激素受体（ER）表达和ER多态性有助于多种激素敏感疾病，包括认知能力下降。我们假设ER1和ER2的差异表达与E2的水平相互作用，从而有助于1）与年龄相关的记忆缺陷的病因，2）E2 E2介导的突触发生的丧失，以及3）E2治疗窗口的关闭。 AIM 1将与病毒载体结合老化的ER1和ER2基因敲除小鼠，以影响ER表达，并系统地执行行为，分子和电生理测定法以检验该假设。 AIM 2将采用海马病毒递送向量来增加或减少年轻，中年龄和老年大鼠的ER1或ER2，并将使用行为和分子测定法来测试以ER1/ER2表达的比率恢复了海马功能的假设。 AIM 3将采用病毒向量来改变ER1或ER2的表达，并将检验ER表达的假设有助于快速E2信号的年龄相关变化。敲除小鼠和病毒载体基因递送提供了新的方法来检验ER表达是海马衰老的促成因子的假设。总之，这些研究将决定改变ER1或ER2表达水平是否对于与年龄相关的记忆下降，E2诱导的突触发生以及E2治疗窗口的关闭是否重要，并将为发展疗法的发展提供基础，以减慢或预防与年龄相关的疾病和与年龄相关的疾病相关的认知能力下降或相关疾病。