Anti-inflammatory properties of estradiol during stroke

雌二醇在中风期间的抗炎特性

基本信息

批准号：
7652502
负责人：
Candice Brown
金额：
$ 5.29万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7652502
关键词：
Adult Affect Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Basic Science Brain Brain Injuries Caspase Cell Death Cerebral Ischemia Clinical Complex Data Disease Estradiol Estrogens Female Gene Expression In Situ Nick-End Labeling Incidence Inflammation Inflammatory Inflammatory Response Injury Ischemic Penumbra Ischemic Stroke Knockout Mice Lead Long-Term Effects Measures Mediating Menopause Middle Cerebral Artery Occlusion Modeling Molecular Mechanisms of Action Mus Nerve Degeneration Nervous System Trauma Neuraxis Neurodegenerative Disorders Neuroprotective Agents Pathway interactions Pattern Physiological Postmenopause Production Property Rate Risk Role Signal Pathway Staining method Stains Stimulus Stroke Testing Therapeutic Effect Woman Women&apos s Health Work Writing aging brain caspase-8 caspase-9 chemokine cytokine human NOS2A protein neuron apoptosis older women protein expression reproductive reproductive function

项目摘要

DESCRIPTION (provided by applicant): Menopause marks an important transition in females that affects both reproductive and non-reproductive function. The extended period of hypoestrogenicity in post-menopausal women profoundly affects the central nervous system by modifying multiple brain functions, increasing the incidence of neurodegenerative diseases, and increasing the risk of ischemic stroke in older women. Several studies have shown that physiological concentrations of 17beta-estradiol (E2) protect against delayed cell death in stroke models and serve an anti-inflammatory role in the central nervous system (CMS.) To further examine the dynamic and complex relationship between E2, inflammation, and apoptosis during stroke, this proposal will test the hypothesis that physiological concentrations of E2 decrease inflammation leading to apoptotic cell death. This hypothesis will be tested in ovariectomized (OVX) and OVX + E2 - treated C57BL/6J (WT) and inducible nitric oxide synthase knockout (iNOSKO) mice using a model of permanent middle cerebral artery occlusion. Three critical components of the ischemic inflammatory response, i.e. 1) microglial activation, 2) inducible nitric oxide synthase gene expression, and 3) production of cytokines and chemokines, will be measured to determine to determine their ability to potentiate two markers^of apoptosis, i.e. 1) TUNEL staining and 2) caspase-8 and caspase-9 activation. This set of studies will enable us to determine: 1) how these three components of inflammation contribute to apoptotic cell death, 2) whether the intrinsic or extrinsic caspase pathways are involved, and 3) the neuroprotective mechanisms utilized by E2 to preserve the ischemic penumbra during stroke. Taken together, these studies will deepen our understanding of the complex neurprotective mechanisms employed by E2 in the adult and aging brain. Lay Summary After menopuase, the brain is particularly vulnerable to the long-term effects of hypoestrogenicity, as several studies have shown that low, physiological levels of 17beta-estadiol are capable of protecting the brain from injury and disease. Using a model of middle cerebral artery occlusion, these studies will determine the therapeutic effects of low, physiological levels of estradiol as a neuroprotectant from the multiple inflammatory stimuli that lead to programmed cell death of neurons during stroke. Completion of these studies will enhance our understanding of the complex ways that 17beta-estradiol protects during neurological injury.

描述（由申请人提供）：更年期标志着女性的重要过渡，影响生殖功能和非生殖功能。绝经后妇女的低雌激素性长期通过改变多种脑功能，增加神经退行性疾病的发生率，并增加老年女性缺血性中风的风险，从而深刻影响中枢神经系统。几项研究表明，17β-雌二醇（E2）的生理浓度可预防中风模型中的延迟细胞死亡，并在中枢神经系统（CMS。）中发挥抗炎作用，以进一步检查E2，炎症，炎症和凋亡之间的动态和复杂关系，该提议将测试该假设的Prysication Plentication Eapepation apepation tad降低了E2降低的浓度。该假设将在卵巢切除术（OVX）和OVX + E2 - 处理过的C57BL/6J（WT）和可诱导的一氧化氮合酶基因敲除（Inosko）小鼠中使用永久性中大脑中部动脉闭塞模型。缺血性炎症反应的三个关键成分，即1）小胶质激活，2）可诱导的一氧化氧化物合酶基因的表达和3）生产细胞因子和趋化因子，以确定确定其能够增强凋亡的两个标记物^的能力，即。这组研究将使我们能够确定：1）这三个炎症成分如何促进凋亡细胞死亡，2）是否涉及固有的或外在的caspase途径，以及3）E2在Streoke期间使用E2使用的神经保护机制。综上所述，这些研究将加深我们对E2在成人和衰老大脑中采用的复杂神经增强机制的理解。绝经后的摘要，大脑特别容易受到低雌激素的长期影响，因为一些研究表明，低生理水平的17beta-甲二醇水平能够保护大脑免受损伤和疾病的侵害。这些研究使用脑动脉闭塞的模型，将确定低生理水平的雌二醇水平作为从多种炎症性刺激的神经保护剂的治疗作用，从而导致中风过程中神经元的编程细胞死亡。这些研究的完成将增强我们对17beta-雌二醇在神经损伤过程中保护的复杂方式的理解。