Glembotski Lab >> Research >> ATF6 Activation
Pharmacological Activation of Adaptive ATF6 in the Heart and Brain:
Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed
in vivo. In recent research done in the Glembotski lab, we used a mouse model of myocardial ischemia/reperfusion to show that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion with a new drug candidate we discovered in collaboration with scientists at The Scripps Research Institute, code named 147, transcriptionally reprogrammed proteostasis, ameliorated damage and preserved heart function in mice.
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These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 was also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a first-in-class proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.
