Protein folding in the endoplasmic reticulum (ER) is indispensable for the life of the cell and constantly chal- lenged by physiological demands and environmental stressors. When the homeostasis of ER protein folding is perturbed, a potentially lethal condition, known as ER stress, is ignited. To mitigate ER stress, a set of con- served ER membrane-associated sensors prioritizes the production of ER foldases and disposal of chronically misfolded proteins. When these adaptive responses are insufficient, the UPR activates pro-cell death process- es. Due to its critical housekeeping roles, the UPR is essential during growth of multicellular organisms and insufficiency leads to harmful conditions in humans, including diabetes, neurodegeneration, and cancer. For decades the UPR has been studied mainly in vitro, in unicellular model organisms and in differentiated cell lines, which can survive UPR insufficiency or are unable to recapitulate the complexity of whole multicellular organisms. Because of this, the design of effective medical therapies targeting UPR-associated diseases re- quires whole-body UPR models where it is possible to develop a mechanistic understanding of the impact of the UPR in growth, stress resistance and pro-death decisions. My long-term research goal is to develop an evolutionarily distinct model system with unique advantages for uncovering the UPR in a whole-body context to formulate a comprehensive understanding of this essential sig- naling pathway in vivo. Towards this goal, our research addresses fundamental knowledge gaps of the UPR in the plant model species Arabidopsis thaliana, because of the conservation of plant and metazoan UPRs and the vast genetics and genomics resources that we have developed and leveraged to study the UPR in whole- body context. Moving forward, we will build upon our exciting new findings, which support the existence of novel signal transduction pathways depending upon the conserved UPR sensors in growth and stress, as well as newly identified effectors of ER stress-related cell death in conditions of unresolvable ER stress in vivo. Specifically, we will focus on 1) the role of protein phosphorylation changes depending on the most conserved UPR sensor, the protein kinase and ribonuclease IRE1, in growth and ER stress mitigation; 2) the characteri- zation of novel non-redundant effectors of cell death discovered through a whole-body forward genetics screen, and 3) the mechanisms which underlie the unique signal transduction pathways of the conserved UPR transcription factors. These efforts will 1) define new non-conventional mechanisms that modulate ER stress response; 2) identify critical cell fate effectors with a functional relevance for unresolved ER stress survival in vivo, and 3) expand the frontiers of the understanding of UPR signal transduction at the intersection with other biological pathways operating in a whole-body system. In the long term, our research will contribute to the knowledge of the UPR at the cellular level and significantly advance our understanding of the UPR in vivo, thus overcoming bottlenecks in formulating effective therapeutics to ameliorate human conditions linked to the UPR.

NARRATIVE This project focuses on largely unexplored mechanisms that multicellular eukaryotes have evolved to grow and protect themselves from death and diseases caused by insufficiency and defects in secretory protein synthesis. To achieve our goals, we will harness the power of the genomic resources and molecular tools of the model plant species Arabidopsis thaliana, which allow genetic and advanced analyses that are impossible to perform in humans and whole-body mammalian models. By studying the signaling pathways of conserved sensors that monitor the homeostasis of secretory protein synthesis, this work will reveal new mechanisms that coordinate growth, stress responses and cell fate decisions and thus improve our understanding of human growth and disease.