Novel Mechanistic Targets of Steroid Hormones in the Brain

描述(由申请人提供)：该计划项目的总体目标是识别和表征雌激素和孕激素具有神经保护作用的新的和可替代的机制靶点。这项研究计划是由提高我们对类固醇激素神经生物学的理解的迫切需要推动的，这一需求在女性健康倡议记忆研究的结果之后变得明显，该研究发现雌激素和/或孕激素的影响与预期相反。为了满足这一需求，我们组织了一个研究计划，由4个高度互动的研究项目和2个支持性核心组成。这些项目中提出的研究向该领域提出了挑战，认为新的膜PR(项目1)、线粒体定位的雌激素受体(项目2)、细胞内钙通道(包括IPS受体和新的线粒体Ryanodine受体)以及以前被忽视的自然产生的雌激素17a-E2(项目4)是神经保护和/或神经发生的关键角色。支持这些项目的将是行政核心(核心A)，它不仅监督研究计划，还将为项目提供生物统计学支持和共同的动物模型(经历了短暂脑缺血的卵巢切除动物)，后者作为单个项目中进行的研究的集成点。此外，质谱学核心(核心B)将通过提供强大的工具来评估大脑类固醇水平，并对蛋白质及其翻译后修饰进行常规识别和/或量化，从而为所有四个项目提供服务，这将有助于增强该计划确定雌激素和孕激素相关机制目标的能力。通过这项拟议研究的成功完成，我们有望确定与雌激素和黄体酮的保护作用相关的神经保护级联反应中的关键角色。特别是，我们将确定最具保护性的激素及其重要的细胞内靶点，这些靶点对于保护神经组织至关重要，反过来，可以利用这些荷尔蒙来开发更安全、更有效的治疗策略，用于治疗更年期和年龄相关疾病，如阿尔茨海默病，其发病率和风险在绝经后增加。

DESCRIPTION (provided by applicant): The overall goal of this program project is to identify and characterize new and alternative mechanistic targets by which estrogens and progestins are neuroprotective. This program of research is driven by a critical need to improve our understanding of steroid hormone neurobiology, a need that became evident following the results of the Women's Health Initiative Memory Study that identified effects of estrogen and/or progestins that were contrary to expectation. To address this need, we have organized a program of research consisting of 4 highly interactive research projects and 2 supportive cores. The studies proposed in these projects challenge the field to consider a novel membrane PR (Project 1), a mitochondria-localized estrogen receptor (Project 2), intracellular Ca2+channels, including IPS receptors and a novel mitochondrial ryanodine receptor (Project 3), and a previously ignored, naturally occurring estrogen, 17a-E2 (Project 4), as critical players in neuroprotection and/or neurogenesis. Supporting these projects will be the Administrative Core (Core A) that not only oversees the program of research, but will also provide biostatistical support and a common animal model (ovariectomized animals that have undergone transient cerebral ischemia) to the projects, the latter serving as a point of integration for the research performed in the individual projects. In addition, the Mass Spectrometry Core (Core B) will serve all 4 projects by providing powerful tools to assess brain steroid levels and for the routine identification and/or quantification of proteins and their posttranslational modifications, which will serve to enhance the Program's ability to define relevant mechanistic targets of estrogens and progestins. Through the successful completion of the proposed research, we expect to have identified key players in the neuroprotection cascade relevant to the protective effects of estrogen and progesterone. In particular, we will have identified the most protective hormone along with their important intracellular targets that are critical for protecting neural tissue, which can in turn, be exploited for the development of safer and more effective therapeutic strategies for treating the menopause and age associated disorders such as Alzheimer's disease, whose incidence and risk increases in the postmenopausal period.