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），不仅监督研究计划，而且还将为项目提供生物统计支持和共同的动物模型（经历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整合点。此外，质谱核心（核心B）将通过提供强大的工具来评估大脑类固醇水平以及蛋白质及其翻译后修饰的常规识别和/或定量，为所有4个项目服务，这将有助于增强该计划的能力定义相关的雌激素和孕激素的机制目标。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，这可以反过来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。 主要研究者：主要研究者Meharvan Singh博士是一位非常有才华的研究者。 他完成了博士学位。1994年在盖恩斯维尔的佛罗里达大学获得神经药理学学位，随后在哥伦比亚大学获得为期三年的博士后研究金。 自2001年以来，他一直在北德克萨斯大学（UNT）任教，目前担任副教授。 Singh博士有资格担任该项目的主任，并领导他一直推动的拟议研究。 审查组成部分 核心A：管理核心; MEHARVAN SINGH博士 描述（由申请人提供）： 行政核心将管理计划项目的进展，该项目的直接目标是发现大脑中类固醇激素的新机制靶点。行政核心有四个具体目标：目标1：核心将全面负责计划项目的管理，并将聘请一名有才华的行政助理来管理计划项目的日常活动。此外，还设立了3个委员会，向主任提供咨询意见。目标2是管理计划项目的财务方面。这将包括建立项目和核心账户、核对账户、向研究者提供预算报告、在需要时订购试剂和供应品、跟踪订单、向健康科学中心以及NIA人员报告支出。目标3是管理项目和核心之间的高水平交互。这将包括促进/协调科学思想的交流（通过定期会议）以及必要时的资源共享。此外，行政核心将有三个主要的次级组成部分，它们将支持和管理项目之间的互动。第一个小组将向所有项目提供统计支助，包括协助对所产生的数据进行事后分析，并探讨各个项目所产生的数据集之间的相互关系。第二个是采购、维护和分配动物到项目中，并作为本研究计划中常见动物模型（经历短暂脑缺血的卵巢切除小鼠）生成的集中资源。第三个项目将提供数据库支助，维持一个网上数据库，对方案项目提供的资源进行编目，并为调查人员分享数据提供一个安全的网站。目标4是为项目调查人员之间以及项目调查人员与UNT健康科学中心社区之间的智力互动创造一个环境。许多机制已经到位或正在发展，以促进这样的环境，包括设施，教师和活动的持续发展研究所内的老龄化和阿尔茨海默氏病研究和妇女健康中心在校园内。

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. PRINCIPAL INVESTIGATOR: The Principal Investigator, Dr. Meharvan Singh, is a highly talented investigator. He completed his Ph.D. degree in Neuropharmacology from the University of Florida, Gainesville in 1994 followed by a three year postdoctoral fellowship at Columbia University. He has been on the faculty of the University of North Texas (UNT) since 2001, where he currently holds an associate professorship. Dr. Singh is qualified to serve as the director of this program and lead the proposed study for which he has been the driving force. REVIEW OF THE COMPONENTS CORE A: ADMINSTRATIVE CORE; DR. MEHARVAN SINGH DESCRIPTION (provided by applicant): The Administrative Core will manage the progress of the Program Project, which has the immediate goal of discovering novel mechanistic targets of steroid hormones in the brain. The Administrative Core has 4 Specific Aims: Aim 1: The Core will hold overall responsibility for the administration of the Program Project and will employ a talented administrative assistant to manage the day-to-day activities of the Program Project. In addition, 3 committees have been established to provide advice to the Director. Aim 2 is to manage the fiscal aspects of the Program Project. This will include setting up Project and Core accounts, reconciling accounts, providing budget reports to the investigators, ordering reagents and supplies when needed, tracking orders, reporting expenditures to the Health Science Center as well as NIA personnel. Aim 3 is to manage the high level of interactions between Projects and Cores. This will include facilitating/coordinating the exchange of scientific ideas (through regular meetings) as well as the sharing of resources, when needed. Further, there will be three major subcomponents of the Administrative Core that will support and manage the interactions between projects. The first will provide statistical support to all projects, including providing assistance with post hoc analyses of the data generated, and exploring correlations between the data sets generated by the individual projects. The second will be to procure, maintain and distribute animals to the projects and serve as a centralized resource for generation of the common animal model within this program of research (the ovariectomized mouse that has undergone transient cerebral ischemia). The third will provide database support by maintaining a web-based database that catalogues the resources available through the Program Project, and also provides a secure site for sharing of data among investigators. Aim 4 is to foster an environment for the intellectual interactions among program investigators, and between program investigators and the UNT Health Science Center community. Numerous mechanisms are in place or in development to foster such an environment, including the continued development of facilities, faculty and activities within the Institute for Aging and Alzheimer's Disease Research and the Center for Women's Health on campus.