Abstract
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.
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Acknowledgements
We thank I. Hairston for assistance with statistical analysis; S. Brooks, I. Zemlyac and H. Wang for technical assistance with cell cultures; G. Greene for the human ERα cDNA; K. Yamamoto for the rat GR cDNA; and Z. Krozowski for the 11βHSD2 cDNA. This work was supported by a US National Institutes of Health grant and by the Adler foundation. D.K. was supported by the Human Frontier Science Program long-term fellowship and the Life Science Research Foundation fellowship. W.O.O. was supported by a National Research Service Award.
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Supplementary Figure 1
Each gene of interest was cloned downstream of the HSV a4 promoter of pa22-eGFP. This vector is packaged into HSV1 amplicons via the "a" packaging sequence. In an additional construct set the ER/GR chimera and dominant negative GR genes were cloned to create eGFP fusion proteins. (GIF 4 kb)
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Kaufer, D., Ogle, W., Pincus, Z. et al. Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nat Neurosci 7, 947–953 (2004). https://doi.org/10.1038/nn1296
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DOI: https://doi.org/10.1038/nn1296
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