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治疗在减少与年龄相关的脑功能障碍发生率方面的益处（包括降低阿尔茨海默病（AD）的风险），但妇女健康倡议（WHl）的结果却提出了相反的建议，并使该领域对激素治疗的未来感到不安。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减少大脑对类固醇激素的保护性反应，这表明雌激素和/或黄体酮的治疗机会窗口是有限的。在资助的第一阶段（4年），该项目试图确定和表征雌激素和黄体酮影响大脑的新的和可替代的机制靶点。目的是对类固醇激素的神经生物学有一个更广阔的视角，并更好地理解这些激素如何保护大脑免受与年龄和年龄相关的疾病（如阿尔茨海默病）有关的损害。这些研究是成功的，并表明膜孕酮受体，线粒体定位雌激素受体和细胞内Ca2+通道（IP3受体和Ryanodine受体）是雌激素和/或孕酮的关键靶点（P4），特别是在脑保护的背景下。在这个竞争性更新中，我们建议应用我们在第一期资助中的发现来测试我们的整体假设，即表达和/或功能

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.