Speaker: R. Luke Wiseman, Professor, Scripps Research

The unfolded protein response (UPR) is the primary stress-responsive signaling pathway responsible for regulating endoplasmic reticulum (ER) and global cellular physiology in response to ER stress. The UPR comprises three integrated signaling pathways activated downstream of the ER stress-sensing proteins IRE1, PERK, and ATF6. Imbalances in UPR signaling are implicated in the pathogenesis of numerous, etiologically-diverse diseases, including many neurodegenerative diseases, protein misfolding diseases, metabolic diseases, and inflammatory diseases. This has led to significant interest in establishing pharmacologic strategies to selectively modulate IRE1, ATF6, or PERK signaling to both ameliorate pathologic imbalances in UPR signaling implicated in these different diseases and define the importance of the UPR in diverse cellular and organismal contexts.Here, I will discuss our work in identifying and developing compounds that selectively activate protective UPR signaling pathways regulated downstream of IRE1 and ATF6. In this presentation, I will describe how our screening strategy prioritizes compound selectivity for specific UPR pathways and the importance of this prioritization for selecting compounds that can be applied to study the functional consequences of UPR signaling in both in vitro and in vivo models. Further, I will discuss how these compounds have improved our ability to probe the functional and therapeutic implications of UPR signaling in cellular and mouse models of different diseases including obesity-related disorders and inflammatory diseases.