CORTICOSTEROID RECEPTORS AND NEURONAL VIABILITY

本项目的长期目标是了解皮质类固醇（CORT）在海马神经元活力中的作用。正常的衰老、压力和长期疾病会导致CORT分泌过多，这与神经元氧化损伤增加、海马神经元丢失和认知障碍有关。 相反，有证据表明，海马颗粒细胞和锥体细胞的存活需要低水平的CORT。 高亲和力、低容量盐皮质激素受体（MR）和低亲和力、高容量糖皮质激素受体（GR）介导CORT效应。该提案的具体目的是解决MR介导CORT的神经保护作用的假设，而CORT通过GR的作用使神经元更容易受到潜在的毒性挑战。 特异性目的1通过在谷氨酸盐、星形孢菌素或炎性细胞因子激发前长期用MR和GR激动剂/拮抗剂处理的原代胎海马培养物中定量神经元死亡来直接测试该假设。具体目标2将在神经元活力改变与MR和GR相关的神经保护和/或促死基因产物表达和转录因子可用性变化相关时检验该假设。 具体目标3将检验MR和GR分别通过促进和破坏线粒体完整性而差异性地影响神经元耐受损伤的能力的假设。

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.