Novel Mechanistic Targets of Steroid Hormones in the Brain

描述（由申请人提供）：本项目的总体目标是确定和表征雌激素和黄体酮具有神经保护作用的新的和可选的机制靶点。这个研究项目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，这种需要在妇女健康倡议记忆研究的结果之后变得明显，该研究确定了雌激素和/或黄体酮的作用与预期相反。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个支持性核心组成的研究计划。这些项目提出的研究挑战了该领域考虑新的膜PR（项目1），线粒体定位的雌激素受体（项目2），细胞内Ca2+通道，包括IPS受体和一种新的线粒体ryanodine受体（项目3），以及以前被忽视的自然发生的雌激素17a-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），它不仅监督研究项目，还将为项目提供生物统计学支持和通用动物模型（经历过短暂性脑缺血的卵巢切除动物），后者将作为单个项目研究的整合点。此外，质谱核心（Core 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，并为蛋白质及其翻译后修饰的常规鉴定和/或定量提供工具，这将有助于提高该项目确定雌激素和黄体酮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黄体酮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，这些靶点对保护神经组织至关重要，反过来，可以用于开发更安全、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. 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.