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: 7244812
• 负责人: Meharvan Singh
• 金额: $ 134.11万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244812
• 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. 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.

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。 首席调查员：首席调查员Meharvan Singh博士是一位才华横溢的调查员。他于1994年在盖恩斯维尔的佛罗里达大学获得神经药理学博士学位，随后在哥伦比亚大学获得了三年的博士后奖学金。自2001年以来，他一直在北得克萨斯大学(UNT)任教，目前在那里担任副教授。辛格博士有资格担任这个项目的负责人，并领导他一直推动的拟议中的研究。 回顾这些组件 核心A：行政核心；梅尔万·辛格博士 描述(由申请人提供)：行政核心将管理该计划项目的进展，该计划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4个具体目标：目标1：核心将全面负责方案项目的管理，并将雇用一名有才华的行政助理来管理方案项目的日常活动。此外，还设立了3个委员会，向署长提供咨询意见。目标2是管理方案项目的财务方面。这将包括建立项目和核心账户，对账，向调查人员提供预算报告，在需要时订购试剂和用品，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级别交互。这将包括促进/协调科学思想的交流(通过定期会议)以及在需要时共享资源。此外，行政核心将有三个主要的子组成部分，用于支持和管理项目之间的互动。第一个项目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。第二项工作是为项目采购、维护和分发动物，并作为该研究项目中常见动物模型(短暂性脑缺血去卵巢小鼠)生成的集中资源。第三个将提供数据库支持，维持一个网络数据库，编目通过方案项目提供的资源，并提供一个安全的网站，供调查人员共享数据。目标4是为项目调查人员之间以及项目调查人员和UNT健康科学中心社区之间的智力互动创造一个环境。许多机制已经建立或正在发展中，以促进这种环境，包括在老龄和阿尔茨海默氏症研究所和校园妇女健康中心内继续发展设施、师资和活动。