ESTROGEN-REGULATED PLASTICITY OF HIPPOCAMPAL NEURONS

雌激素调节的海马神经元的可塑性

• 批准号: 6869954
• 负责人: Bruce S. McEwen
• 金额: $ 21.64万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869954
• 关键词: BCL2 gene /protein; NMDA receptors; aging; calcium flux; estrogens; female; hippocampus; hormone regulation /control mechanism; inflammation; laboratory rat; neural plasticity; neuroprotectants; neurotoxins; progesterone; receptor expression; serine threonine protein kinase; synaptogenesis; tissue /cell culture

In order to fully understand changes in brain function during aging, it is necessary to understand how hormones that decline with age normally regulate and maintain structural and functional plasticity and resilience of the adult brain. Estradiol (E) is the best studied hormone with respect to cognitive decline and Alzheimer's disease. Yet, even then, we are largely ignorant about how the aging brain responds to E at the cellular, molecular and anatomical levels and how E regulated plasticity and neuroprotective actions may change with age. Moreover, we need to know whether E has neuroprotective actions that are related to their ability to regulate structural and functional plasticity and to contain the production in brain of potentially damaging molecules such as cytokines that rises with age. The main objective of this project is to carry out in vitro studies of the signaling pathways at the cellular and molecular level by which E causes synapse formation in hippocampal and cortical neurons and also protects cells against damage and death. The main hypothesis is that E-induction of dendritic spines is a mechanism that not only enhances neural function and memory processes but also confers protection of neurons from excitotoxic damage, in part because both involve operation of the same signaling pathways. Collaborative studies will determine the relevance of these mechanisms to the studies of the hypothesized age-related decline in E-induced synapse formation in the aging rat and primate brain which are being studied in other components of this program project. The E-regulated signaling pathways increase the options for intervention by estrogens or modified estrogens. Because hormone therapy (HT) is under close clinical scrutiny, it is critical to obtain a more detailed, mechanistic understanding of how estrogens affect the brain in order to provide for more informed approaches to HT and to promote an understanding of successful brain aging. Results from this project and from the PPG as a whole should facilitate identification of specific analogs and other pharmacologic molecules of therapeutic value to the aging process.

为了在衰老过程中充分了解大脑功能的变化，有必要了解随着年龄的增长而下降的激素通常会调节成人大脑的结构和功能可塑性以及弹性。雌二醇（E）是关于认知能力下降和阿尔茨海默氏病的最佳研究激素。然而，即使到那时，我们在很大程度上对衰老的大脑在细胞，分子和解剖学水平以及E调节的可塑性和神经保护作用如何随着年龄的变化而变化的大脑对E的反应却一无所知。此外，我们需要知道E是否具有与它们调节结构和功能可塑性的能力相关的神经保护作用，并包含潜在破坏性分子的大脑中的产生，例如随着年龄的增长而增加的细胞因子。该项目的主要目的是在细胞和分子水平上对信号传导途径进行体外研究，E导致E引起突触 海马和皮质神经元中的形成，还保护细胞免受损伤和死亡的影响。主要的假设是树突状棘的电子诱导是一种机制，不仅可以增强神经功能和记忆过程，而且还赋予神经元免受兴奋性毒性损伤的保护，部分原因是两者都涉及相同信号通路的操作。协作研究将确定这些机制与假设年龄相关的老年大鼠突触形成和灵长类动物大脑中电子诱导的突触形成下降的相关性，这些研究正在该计划项目的其他组件中研究。电子调节 信号通路增加了雌激素或改良雌激素干预的选择。 由于激素疗法（HT）受到临床审查的严格审查，因此至关重要的是，要获得对雌激素如何影响大脑的更详细的机械理解，以便为HT提供更明智的方法并促进对成功的大脑衰老的理解。该项目和PPG的结果应促进衰老过程的特定类似物和其他药理学分子的鉴定。