Deciphering the Dynamics of the Unfolded Protein Response

About This Grant

This project aims to better understand how cells determine their fate when they are under stress, specifically stress in a part of the cell called the endoplasmic reticulum (ER), the cell's power plant, which produces and folds proteins. Since proteins support all cellular functions, the production of properly functioning proteins is critical to cellular health. When the ER becomes overwhelmed due to an increase in protein production needs, it triggers a response called the unfolded protein response (UPR). This type of response plays a crucial role in maintaining cell health. If the UPR goes awry, then cellular fate is altered, potentially leading to cell death. This research project develops new tools that enable the investigation of how genes behave in real-time and create systems that help cells better manage protein production under stress. Unlike older trial and-error methods, these approaches provide precise control over how cells respond, utilizing built-in feedback systems. The results of this project could lead to new ways to engineer healthier, more resilient cells. The highly multidisciplinary research environment provides broadly reaching educational and training opportunities to graduate, undergraduate, and high school students. The secretory pathway is responsible for synthesizing approximately one-third of all proteins in eukaryotic cells. As physiological demands and pathological insults constantly challenge endoplasmic reticulum (ER) homeostasis, the unfolded protein response (UPR) activates adaptive mechanisms to maintain an optimal protein production rate, reacting to diverse stimuli and leading to opposite cell fate decisions (survival or cell death). Current approaches for manipulating the UPR and investigating the link between UPR and cell fate are based on the deregulated or exogenously controlled modulation of specific UPR genes, which results in cell adaptation. This research project uses previously built feedback-regulated cells that detect the UPR status and, in response, modulate specific UPR signaling pathways to mitigate stress and enhance cell viability. This synthetic biology platform is used to investigate the relationship between the temporal progression of the UPR and cell fate. The project also engineers cells that continuously and dynamically adjust the innate cellular capacity to buffer proteotoxic stress in response to diverse stimuli, including environmental stresses (glucose deprivation, oxidative stress), the overexpression of secretory proteins, and viral particle replication and assembly. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.