CORTICOSTEROID RECEPTORS AND NEURONAL VIABILITY

该项目的长期目标是了解皮质类固醇(CORT)在海马神经元存活中的作用。正常的衰老、应激和长期疾病会产生皮质醇的高分泌，这与神经元氧化损伤、海马神经元丢失和认知障碍有关。相反，有证据表明，低水平的皮质醇是海马颗粒细胞和锥体细胞生存所必需的。高亲和力、低容量的盐皮质激素受体(MR)和低亲和力、高容量的糖皮质激素受体(GR)介导CORT效应。这项提议的具体目的是解决这样一种假设，即MR介导皮质醇的神经保护作用，而皮质醇通过GR的作用使神经元更容易受到潜在毒性挑战的影响。具体目标1通过量化在谷氨酸、星形孢子素或炎性细胞因子攻击之前长期使用MR和GR激动剂/拮抗剂处理的原代胎儿海马区神经元死亡来直接检验这一假说。特定目标2将检验这一假设，即神经元活性的改变与MR和GR相关的神经保护和/或促死亡基因产物的表达变化以及转录因子的可获得性相关。具体目标3将测试这一假设，即MR和GR分别通过促进和破坏线粒体的完整性来不同地影响神经元抵御侮辱的能力。

The long term goal of this project is to understand the role of corticosteroids (CORT) in the viability of hippocampal neurons. Normal aging, stress, and prolonged illness produce CORT hypersecretion, which has been associated with increased oxidative damage to neurons, hippocampal neuron loss, and cognitive impairment. Conversely, there is evidence that low levels of CORT are required for the survival of hippocampal granule cells and pyramidal cells. The high affinity, low capacity mineralocorticoid receptor (MR) and the low affinity, high capacity glucocorticoid receptor (GR) mediate CORT effects. The specific aims of this proposal address the hypothesis that MR mediates neuroprotective effects of CORT, while CORT action through GR renders neurons more susceptible to potentially toxic challenges. Specific Aim 1 tests this hypothesis directly by quantitating neuronal death in primary fetal hippocampal cultures treated chronically with MR and GR agonists/antagonists prior to glutamate, staurosporine or inflammatory cytokine challenge. Specific Aim 2 will test the hypothesis at altered neuronal viability correlates with MR- and GR-associated changes in the expression of neuroprotective and/or death-promoting gene products and transcription factor availability. Specific Aim 3 will test the hypothesis that MR and GR differentially affect neuronal ability to withstand insults by promoting and disrupting, respectively, mitochondrial integrity.