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首页> 外文学位 >Glucocorticoids regulate the expression of NGF, bFGF, and S100-beta in cultured hippocampal astrocytes: Impact on hippocampal neuron survival.
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Glucocorticoids regulate the expression of NGF, bFGF, and S100-beta in cultured hippocampal astrocytes: Impact on hippocampal neuron survival.

机译：糖皮质激素调节培养的海马星形胶质细胞中NGF，bFGF和S100-beta的表达：对海马神经元存活的影响。

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摘要

Glucocorticoids play complex roles in the development, survival, and aging of hippocampal neurons; however, the mechanisms underlying these phenomena are unclear. Although several hypotheses have been proposed and tested, few studies have focused on how glucocorticoids influence neuron-astrocyte interactions. Astrocytes synthesize and secrete a wide variety of neurotrophic factors, through which they may regulate neuronal activity and survival. Therefore, I hypothesize that glucocorticoids regulate the expression of astrocyte-derived neurotrophic factors in the hippocampus. This affects the ability of astrocytes to support neuron survival, which may, in turn, contribute to the complex roles that glucocorticoids play in development, maintenance and aging of the hippocampus. To test the hypothesis, I monitored the effects of glucocorticoids on gene expression of three astrocyte-derived neurotrophic factors which are known to be important for hippocampal neuron development and survival, NGF{dollar}beta{dollar}, bFGF and S100{dollar}beta{dollar}, in cultured hippocampal astrocytes. Enriched type I astrocyte cultures from hippocampus were treated with dexamethasone, a synthetic glucocorticoid. Neurotrophic factor mRNAs were measured by solution hybridization-RNase protection assays. Dexamethasone suppressed NGF{dollar}beta{dollar} mRNA. In contrast, it stimulated bFGF mRNA levels and induced a biphasic response in S100{dollar}beta{dollar} gene expression. Furthermore, I monitored the protein levels of these three neurotrophic factors using Sandwich ELISA. Some of the dexamethasone-induced changes in NGF{dollar}beta{dollar}, bFGF, and S100{dollar}beta{dollar} mRNA levels were translated into parallel changes in their intracellular protein levels or in their levels in the conditioned medium. These results demonstrate that glucocorticoids differentially regulate the expression of important neurotrophic factors in hippocampal astrocytes in vitro. In addition, I observed the impact of glucocorticoid-induced changes in astrocytes on hippocampal neuron survival and on the vulnerability of the neurons to excitatory stimuli. Hippocampal neuronal cell cultures were treated with the conditioned medium which was collected from purified type I hippocampal astrocyte cultures that had been treated with dexamethasone. Neuron survival rates were calculated by counting viable neurons in cell culture. Conditioned medium from dexamethasone-treated astrocytes increased neuron survival under basal conditions; whereas, it decreased the survival after exposure to glutamate. These results indicate dexamethasone affects the ability of astrocyte-conditioned medium to support neuron survival and the ability of astrocyte-conditioned medium to protect neurons against the excitatory neurotoxicity. At the present time, it is unclear which astrocyte-derived factors are responsible for the dexamethasone effects; however, it is possible that the changes in the expression of NGF, bFGF, and S100{dollar}beta{dollar} which I observed previously are involved. Together, these studies suggest that one of the possible mechanisms underlying the complex roles of glucocorticoids played in the hippocampus is through the regulation of astrocyte-derived neurotrophic factors.
机译：糖皮质激素在海马神经元的发育，存活和衰老中起着复杂的作用。但是，这些现象的潜在机制尚不清楚。尽管已经提出并检验了几种假设，但很少有研究集中在糖皮质激素如何影响神经元-星形细胞相互作用上。星形胶质细胞合成并分泌多种神经营养因子，通过它们可以调节神经元的活动和存活。因此，我推测糖皮质激素调节海马中星形胶质细胞源性神经营养因子的表达。这会影响星形胶质细胞支持神经元存活的能力，进而可能加剧糖皮质激素在海马发育，维持和衰老中所起的复杂作用。为了验证这一假设，我监测了糖皮质激素对三种星形胶质细胞衍生的神经营养因子的基因表达的影响，这些因子对海马神经元的发育和存活至关重要，NGF {dollar} beta {dollar}，bFGF和S100 {dollar} beta {美元}，在培养的海马星形胶质细胞中。用地塞米松（一种合成的糖皮质激素）处理海马中富集的I型星形胶质细胞培养物。通过溶液杂交-RNase保护试验测量神经营养因子的mRNA。地塞米松抑制NGF {dollar} beta {dollar} mRNA。相反，它刺激bFGF mRNA水平并诱导S100 {dollar} beta {dollar}基因表达中的双相反应。此外，我使用夹心ELISA监测了这三个神经营养因子的蛋白质水平。地塞米松诱导的NGF {beta}，bFGF和S100 {beta} {dollar} mRNA水平中的某些变化被转化为细胞内蛋白质水平或条件培养基中水平的平行变化。这些结果表明，糖皮质激素在体外差异调节海马星形胶质细胞中重要神经营养因子的表达。此外，我观察了糖皮质激素诱导的星形胶质细胞变化对海马神经元存活以及神经元对兴奋性刺激的脆弱性的影响。用条件培养基处理海马神经元细胞培养物，该条件培养基是从已经用地塞米松处理过的纯化的I型海马星形胶质细胞培养物中收集的。通过计数细胞培养物中的存活神经元来计算神经元存活率。来自地塞米松处理的星形胶质细胞的条件培养基在基础条件下增加了神经元存活；而降低了谷氨酸暴露后的存活率。这些结果表明，地塞米松影响星形细胞条件培养基支持神经元存活的能力以及星形细胞条件培养基保护神经元免受兴奋性神经毒性的能力。目前，尚不清楚哪些星形胶质细胞衍生的因子负责地塞米松的作用。但是，可能涉及到我之前观察到的NGF，bFGF和S100 {dollar} beta {dollar}的表达变化。总之，这些研究表明，在海马中发挥糖皮质激素的复杂作用的潜在机制之一是通过星形胶质细胞衍生的神经营养因子的调控。

著录项

  • 作者

    Niu, Helen Hairong.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Biology Animal Physiology.; Biology Molecular.; Biology Neuroscience.; Biology Cell.
  • 学位 Ph.D.
  • 年度 1996
  • 页码 201 p.
  • 总页数 201
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生理学;分子遗传学;神经科学;细胞生物学;
  • 关键词

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