MODULATION OF CNS FUNCTION USING A NOVEL SELECTIVE ESTROGEN (SERM)

使用新型选择性雌激素 (SERM) 调节中枢神经系统功能

• 批准号: 8357790
• 负责人: HENRYK F URBANSKI
• 金额: $ 3.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357790
• 关键词: Adrenal Glands; Adverse effects; Age; Aging; Body Temperature; Cancer Etiology; Clinical; Dehydroepiandrosterone Sulfate; Enzymes; Estradiol; Estrogen Receptor Modulators; Estrogens; Female; Funding; Genes; Goals; Gonadal Steroid Hormones; Grant; Hormone replacement therapy; Impairment; Macaca; Macaca mulatta; Molecular Biology; National Center for Research Resources; Peripheral; Pilot Projects; Postmenopause; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Selective Estrogen Receptor Modulators; Sleep Wake Cycle; Source; Steroids; Tissues; United States National Institutes of Health; Woman; age related; attenuation; cognitive function; cost; dehydroepiandrosterone; neuromechanism; novel; programs; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our ongoing rhesus macaque studies confirm clinical observations that female aging is associated with decreased cognitive function, loss of white matter in the CNS and perturbed sleep-wake cycles. Moreover, these changes are closely associated with a marked attenuation of the circulating levels of estradiol as well as DHEA and DHEA sulfate (DHEAS), two adrenal steroids. It appears that the primate CNS expresses genes that encode key enzymes in the conversion of DHEA/DHEAS to estradiol and that these too show age-related alterations. Hence, a primary goal of our research program is to establish the efficacy of DHEA replacement as a potential therapy for age-associated impairments of the CNS, and importantly, one with less risk of causing cancer in peripheral tissues. In this related pilot study, our goal is to explore an alternate strategy. Namely, to use STX (a novel centrally-acting selectively active estrogen receptor modulator) to overcome age-related, sex-steroid dependent changes within the macaque CNS. This research has the potential to identify a novel hormone replacement therapy (HRT) for use in postmenopausal women - one that has the advantage of acting centrally and without causing unwanted peripheral side-effects. So far, we have found STX to be as effective as estradiol at suppressing core body temperature. Ongoing molecular biology studies are using Affymetrix gene arrays and RT-PCR to elucidate the underlying neural mechanism.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们正在进行的恒河猕猴研究证实了临床观察结果，即女性衰老与认知功能降低，中枢神经系统中的白质损失以及扰动的睡眠效果周期有关。此外，这些变化与两种肾上腺类固醇的循环水平以及DHEA和DHEA硫酸盐（DHEAS）的循环水平明显衰减密切相关。似乎灵长类动物中枢神经系统表达了在DHEA/DHEAS转化为雌二醇中编码键酶的基因，并且这些基因也表现出与年龄相关的改变。因此，我们的研究计划的主要目标是确定DHEA替代的功效，作为CNS年龄相关损伤的潜在疗法，重要的是，在外围组织中引起癌症的风险较小。在这项相关的试点研究中，我们的目标是探索另一种策略。也就是说，使用STX（一种新型的集中作用选择性活跃的雌激素受体调节剂）来克服与年龄相关的性，性依赖性依赖性变化。 这项研究有可能识别一种新型的激素替代疗法（HRT）用于绝经后妇女 - 一种具有中央作用并且不会引起不必要的外围副作用的优势。到目前为止，我们发现在抑制核心体温下，STX与雌二醇一样有效。正在进行的分子生物学研究使用Affymetrix基因阵列和RT-PCR来阐明潜在的神经机制。