Novel Mechanistic Targets of Steroid Hormones in the Brain

描述(由申请人提供)：虽然许多临床前研究支持激素疗法在减少与年龄相关的脑功能障碍的发生率(包括降低阿尔茨海默病(AD)的风险)方面的好处，但妇女健康倡议(WHL)的结果表明情况相反，并使该领域对激素疗法的未来感到不安。然而，WHL的重要警告包括绝经后激素剥夺的持续时间可能会降低大脑对类固醇激素的保护性反应，这表明雌激素和/或孕激素的治疗机会有限的概念。在资助的第一阶段(4年)，该计划项目试图确定和表征雌激素和孕激素影响大脑的新的和可替代的机制靶点。其目的是对类固醇激素的神经生物学实现更广泛的视角，并更好地从概念上理解这些激素如何保护大脑免受与年龄相关的侮辱和与年龄相关的疾病，如阿尔茨海默病。这些研究是成功的，表明细胞膜孕酮受体，一种定位于雌激素受体的线粒体，以及细胞内的钙通道(IP3受体和Ryanodine受体)是雌激素和/或孕酮(P4)的关键靶标，特别是在脑保护的背景下。在这次竞争性更新中，我们建议应用我们在第一个资金阶段的发现来测试我们的总体假设，即表达和/或功能 这些新的靶点决定了大脑对雌激素和P4保护作用的敏感性，从而定义了治疗机会的“关键窗口”。我们的研究团队将通过将他们各自的特定于项目的分析(这些分析本身具有共同的主题，如激素诱导的细胞信号)整合到一个共同的动物模型(OVXed大鼠，由Core B实现)中，然后将结果转化为人类样本(来自手术绝经期女性及其各自的对照-由Core A实现)，从而解决整个假设。拟议研究的成功完成将成为确定扩大治疗窗口的战略的框架。也就是说，有助于维持孕激素受体、线粒体ER和细胞内钙通道的表达和/或功能的干预措施，可能有助于维持大脑对雌激素和P4的反应能力。总而言之，这些策略将导致开发更安全、更有效的治疗策略来治疗更年期，并降低各种大脑疾病(包括AD)的风险，这些疾病的风险在绝经后时期会增加。

DESCRIPTION (provided by applicant): While numerous pre-clinical studies have supported the benefit of hormone therapy in reducing the incidence of age-associated brain dysfunction (including reducing the risk for Alzheimer's disease (AD)), results from the Women's Health Initiative (WHl) have suggested the contrary and left the field unsettled as to the future of hormone therapy. However, important caveats of the WHl include the possibility that the duration of postmenopausal hormone deprivation diminish the protective brain response to steroid hormones, suggesting the concept of a finite therapeutic window of opportunity for estrogens and/or progestins. During the first period (4 years) of funding, this Program Project sought to identify and characterize new and alternative mechanistic targets through which estrogens and progestins affect the brain. The intent was to achieve a broader perspective on the neurobiology of steroid hormones and a better conceptual understanding of how these hormones protect the brain from insults relevant to age and age-associated diseases such as AD. These studies were successful and showed that membrane progesterone receptors, a mitochondria localized estrogen receptor, and intracellular Ca2+ channels (IP3 receptors and Ryanodine receptors) are key targets for estrogens and/or progesterone (P4), particularly within the context of brain protection. In this competitive renewal, we propose to apply our findings from the first period of funding to test our overall hypothesis that the expression and/or function of these novel targets dictate the sensitivity of the brain to the protective effects of estrogens and P4, and therefore define the "critical window" of therapeutic opportunity. Our team of researchers will address the overall hypothesis by integrating their respective Project-specific analyses (which themselves have common themes, such as hormone-induced cell signaling) into a common animal model (the OVXed rat, enabled by Core B), and then translating the results into human samples (brain samples from surgically menopausal women and their respective controls - enabled by Core A). Successful completion of the studies proposed will serve as the framework for defining strategies to expand the therapeutic window. That is, interventions that help maintain the expression and/or function of progesterone receptors, mitochondrial ER¿ and intracellular calcium channels may help maintain the brain's capacity to respond to estrogen and P4. Together, these strategies will lead to the development of safer and more effective therapeutic strategies for treating the menopause and reducing the risk for various brain disorders (including AD) whose risk increases during the post'-menopausal period.