Restructuring the neuronal stress response with anti-glucocorticoid gene delivery
Restructuring the neuronal stress response with anti-glucocorticoid gene delivery
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DOI：
10.1038/nn1296
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发表时间：
2004-09-01
影响因子：
25
通讯作者：
Sapolsky, RM
中科院分区：
文献类型：
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作者：
Kaufer, D;Ogle, WO;Sapolsky, RM
糖皮质激素是应激过程中释放的肾上腺类固醇，会损害神经元在神经损伤中生存的能力。相比之下，雌激素可以保护神经元免受这种损伤。我们设计了三种基因干预措施来控制糖皮质激素的作用，从而减少了它们在体外和体内模型中的有害影响。这些干预措施中最有效的是创建了一个嵌合受体，该受体结合了糖皮质激素受体的配体结合域和雌激素受体的DNA结合域。这种嵌合受体的表达使神经损伤后的海马区损伤面积减少了63%，并通过使糖皮质激素具有保护性而不是破坏性来逆转应激反应的结果。我们的发现阐明了神经元应激反应途径中的三个主要步骤，所有这些步骤都可以进行治疗干预。
Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.