UCUPA · Unraveling the Molecular Changes that Drive the Repression of the Unfolded Protein Response with Ageing
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-09-01 → 2022-08-31
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Unraveling the Molecular Changes that Drive the Repression of the Unfolded Protein Response with Ageing
Ageing is the greatest risk factor for a wide range of diseases, such as dementia, COVID-19, and cardiovascular diseases. According to several governmental reports, it is expected that the European population with more than 65 years old will significantly increase over the next decades. Therefore, it is imperative that we increase our understanding of how humans and animals age, so we can generate novel therapeutic approaches to increase human healthspan and to prevent age-related disorders. The main question that we addressed in this project was to understand why animals lose their ability to sense and respond to stress when they age. With ageing, protein quality control pathways become less efficient, leading to the accumulation of misfolded proteins and toxic aggregates. A conserved hub in the proteostasis network is the UPRER (Unfolded Protein Response of the Endoplasmic Reticulum). Previously, it was identified that the UPRER pathway becomes repressed with ageing in animals, but the molecular mechanism of why its activity decreases with ageing remains elusive. This proposal tries to address this question by (i) Monitoring the activity of the different steps of the IRE-1/XBP-1 axis with ageing, and (ii) Identifying interventions that sustain UPRER activation in older animals and test their impact on lifespan.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- UNITED KINGDOM RESEARCH AND INNOVATION · SWINDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union