Novel Mechanistic Targets of Steroid Hormones in the Brain

描述（由申请人提供）： 这个项目的总体目标是确定和表征新的和替代的机制目标，雌激素和孕激素是神经保护。这项研究计划是由一个关键的需要，以提高我们对类固醇激素神经生物学的理解，需要成为明显的结果后，妇女的健康倡议记忆研究，确定雌激素和/或孕激素的影响是相反的预期。为了满足这一需求，我们组织了一个由4个高度互动的研究项目和2个支持核心组成的研究计划。在这些项目中提出的研究挑战该领域考虑一种新的膜PR（项目1），一种位于子宫内膜的雌激素受体（项目2），细胞内Ca 2+通道，包括IPS受体和一种新的线粒体ryanodine受体（项目3），以及一种以前被忽视的天然雌激素17 a-E2（项目4），作为神经保护和/或神经发生的关键参与者。支持这些项目的将是行政核心（核心A），它不仅负责监督研究计划，还将为项目提供生物统计支持和通用动物模型（经历过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，质谱核心（核心B）将为所有4个项目提供强大的工具，以评估大脑类固醇水平和蛋白质及其翻译后修饰的常规鉴定和/或定量，这将有助于提高该计划确定雌激素和孕激素相关机制靶点的能力。通过成功完成拟议的研究，我们希望能够确定与雌激素和孕激素的保护作用相关的神经保护级联反应中的关键参与者。特别地，我们将鉴定出最具保护性的激素沿着它们的重要的细胞内靶点，所述细胞内靶点对于保护神经组织是至关重要的，这反过来可以被利用来开发更安全和更有效的治疗策略，用于治疗绝经和年龄相关的疾病，例如阿尔茨海默病，其发病率和风险在绝经后时期增加。

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.