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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们正在进行的恒河猴研究证实了女性衰老与认知功能下降、CNS中白色物质丢失和睡眠-觉醒周期紊乱相关的临床观察结果。此外，这些变化与雌二醇以及DHEA和DHEA硫酸盐（DHEAS）（两种肾上腺类固醇）的循环水平的显著衰减密切相关。看来灵长类动物中枢神经系统表达编码DHEA/DHEAS转化为雌二醇的关键酶的基因，这些基因也显示出与年龄相关的变化。因此，我们研究计划的主要目标是确定DHEA替代作为CNS年龄相关损伤的潜在疗法的疗效，重要的是，在外周组织中引起癌症的风险较低。在这项相关的试点研究中，我们的目标是探索一种替代策略。也就是说，使用STX（一种新的中枢作用的选择性活性雌激素受体调节剂），以克服猕猴中枢神经系统内年龄相关的，性类固醇依赖性的变化。 这项研究有可能确定一种用于绝经后妇女的新型激素替代疗法（HRT）-一种具有集中作用而不会引起不必要的外周副作用的优势。到目前为止，我们已经发现STX在抑制核心体温方面与雌二醇一样有效。目前正在进行的分子生物学研究使用Affyrin基因阵列和RT-PCR来阐明潜在的神经机制。

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.