Novel Mechanistic Targets of Steroid Hormones in the Brain

大脑中类固醇激素的新机制目标

• 批准号: 7879950
• 负责人: Meharvan Singh
• 金额: $ 142.91万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879950
• 关键词: Novel; Mechanistic; Targets; Steroid; Hormones

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.

描述（由申请人提供）：该计划项目的总体目标是确定和表征雌激素和孕激素具有神经保护作用的新的和替代的机制目标。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所驱动的，在女性健康倡议记忆研究的结果发现雌激素和/或孕激素的影响与预期相反之后，这种需要变得明显。为了满足这一需求，我们组织了一项研究计划，其中包括 4 个高度互动的研究项目和 2 个支持性核心项目。这些项目中提出的研究挑战该领域，将新型膜 PR（项目 1）、线粒体定位雌激素受体（项目 2）、细胞内 Ca2+ 通道，包括 IPS 受体和新型线粒体兰尼碱受体（项目 3），以及以前被忽视的天然雌激素 17a-E2（项目 4）作为神经保护和/或 神经发生。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，还将为这些项目提供生物统计支持和通用动物模型（经历短暂性脑缺血的卵巢切除动物），后者作为各个项目中进行的研究的整合点。此外，质谱核心（核心B）将为所有4个项目提供强大的工具来评估脑类固醇水平以及蛋白质及其翻译后修饰的常规鉴定和/或定量，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中的关键参与者。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，进而可用于开发更安全、更有效的治疗策略，用于治疗更年期和与年龄相关的疾病，例如阿尔茨海默病，其发病率和风险在绝经后时期会增加。