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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在进行的恒河猴研究证实了临床观察结果，即女性衰老与认知功能下降、中枢神经系统白质丢失和睡眠-觉醒周期紊乱有关。此外，这些变化与循环中雌二醇以及DHEA和DHEAS(两种肾上腺类固醇)的循环水平显著降低密切相关。似乎灵长类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，我们研究计划的一个主要目标是确定DHEA替代疗法作为治疗与年龄相关的中枢神经系统损害的潜在疗法的有效性，而且重要的是，这种疗法在周围组织中引起癌症的风险较低。在这项相关的初步研究中，我们的目标是探索一种替代战略。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与年龄相关的、性类固醇依赖的变化。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)，这种疗法具有集中作用且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；正在进行的分子生物学研究将有助于阐明其潜在的神经机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. 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  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 will help to elucidate the underlying neural mechanism.