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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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新的激素替代疗法（HRT）用于绝经后妇女，具有集中作用的优势，不会引起不必要的外周副作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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, that has the advantage of acting centrally and without causing unwanted peripheral side-effects.