Unraveling the Molecular Changes that Drive the Repression of the Unfolded Protein Response with Ageing

ended

What defines the functional specialization of a cell is its unique proteome. Proteins need to be translated and properly folded to ensure their biological function. Several protein quality control pathways have arisen during evolution, some of them specialized in monitoring protein folding in specific organelles . As a result of ageing, animals lose their ability to protect their proteome, leading to the accumulation of protein aggregates and the onset of age-related disorders. The Unfolded Protein Response (UPR) of the Endoplasmic Reticulum (ER) is a central protein quality control mechanism that declines with ageing. This project will use the nematode Caenorhabditis elegans as a model to understand age-related proteostasis dysfunction. C. elegans offer many advantages over the use of vertebrate models, such as its short lifespan of about two weeks, reduced costs, and fewer ethical issues. We will focus on the UPR pathway, as changes in this pathway have already been implicated in the ageing process itself and in the onset of age-related disorders, such as Alzheimer’s disease. We propose to use CRISPR genome editing to create C. elegans transgenic reporter strains that enable us to track the activity of different UPR signalling molecules using microscopy and molecular biology techniques. We will monitor two central steps of the IRE-1/XBP-1 UPR pathway (1) the activation of the transmembrane sensor protein IRE-1 and (2) the biogenesis of the transcription factor XBP-1s. After age-related changes have been identified, we will use mutagenesis-based screening assays to screen for novel interventions that prevent UPR pathway shutdown. This research will contribute to a better understanding of why ageing occurs, as well as suggesting new therapeutic avenues for age-related disorders. This proposal will also be instrumental for the development and transference of new skills between the host and the applicant that will lead me towards independence.