Mechanisms of translational regulation by the unfolded protein response

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Project Summary/Abstract Summary of Research Project: Protein folding is one of the most critical nodes of cellular health and cells employ dedicated machineries comprised of transcriptional, co-translational and post-translational mechanisms to ensure all proteins are correctly folded and the incorrectly folded proteins are rapidly triaged. The endoplasmic reticulum (ER) is the site of folding and maturation of the majority of transmembrane proteins and secreted proteins, and its dysfunction is linked to a dozen different diseases including diabetes, neurodegenerative diseases and cancer. Recent work suggests that IRE1 is physically linked to the translational machinery. This finding opens an entire new field of translational regulation by IRE1 and possibly by other UPR sensors. In this proposal, I will gain high-resolution insights in this newly discovered mode of translational regulation at the ER. Career Development Plan and Environment: As a graduate student in David Eisenberg’s lab at UCLA, I investigated the toxic conformational states in the protein aggregation pathway using X-ray crystallography. I have continued my training in the field of protein folding by taking a cell biological approach working in the lab of Dr. Peter Walter at UCSF. I will continue my professional development by learning the latest techniques in CryoEM and functional genomics. Under the mentorship of Dr. David Agard, a pioneer in the methods for single-particle cryoEM, Dr. Peter Walter, an expert in the field of UPR and IRE1 biology and with advise and guidance from Dr. Stephen Floor, a functional genomics expert, I will gain significant training that will ultimately help me transition to an independent research career. Career Goals: My career goal is to establish a research program investigating the fundamental mechanisms of protein folding in cells. How cells manage partially folded and misfolded proteins, the mechanism employed to fine-tune translation of specific genes to prevent overwhelming the protein folding machinery and how cells correct chronic build-up of protein aggregates are some of the questions that I will address in my independent research.