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降低年龄相关性脑功能障碍的发生率（包括降低阿尔茨海默病（AD）的风险）方面的益处，但妇女健康倡议（WHl）的结果表明相反，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减少对类固醇激素的保护性脑反应的可能性，这表明雌激素和/或孕激素的有限治疗机会窗口的概念。在第一阶段（4年）的资金，该计划项目寻求确定和表征新的和替代的机制目标，通过雌激素和孕激素影响大脑。其目的是实现对类固醇激素的神经生物学的更广泛的视角，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疾病（如AD）相关的损伤。这些研究是成功的，并表明，膜孕酮受体，线粒体定位的雌激素受体，和细胞内钙离子通道（IP 3受体和Ryanodine受体）是雌激素和/或孕酮（P4）的关键目标，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助期的发现来检验我们的总体假设，即表达和/或功能 这些新的靶点决定了大脑对雌激素和P4的保护作用的敏感性，因此定义了治疗机会的“关键窗口”。我们的研究团队将通过将他们各自的项目特定分析（它们本身具有共同的主题，例如乳腺癌诱导的细胞信号传导）整合到一个共同的动物模型（OVXed大鼠，由Core B启用）中，然后将结果转化为人类样本（来自手术绝经妇女及其各自对照的大脑样本-由Core A启用）来解决整体假设。成功完成拟议的研究将作为确定扩大治疗窗口战略的框架。也就是说，有助于维持孕酮受体，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。总之，这些策略将导致更安全和更有效的治疗策略的发展，用于治疗更年期和降低各种脑部疾病（包括AD）的风险，这些疾病的风险在绝经后时期增加。

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.