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PROMISE

PROMISE

Michael J. Kraakman (ORCID: 0000-0002-5755-0447)
  • Grant DOI 10.55776/PAT4663523
  • Funding program Principal Investigator Projects
  • Status ongoing
  • Start December 1, 2023
  • End November 30, 2026
  • Funding amount € 399,533
  • E-mail

Disciplines

Biology (40%); Medical-Theoretical Sciences, Pharmacy (60%)

Keywords

    Human immunity, Inborn error of immunity, Metabolism, Proteostasis, ER Stress

Abstract

For cells to function, their proteins must be produced without errors, transported to respective cellular compartments, and recycled when necessary. Proteostasis refers to the collective biological processes that perform, control, and fine-tune such important tasks. Given its importance, cells have evolved various elegant and highly interconnected molecular features that permits the rapid adjustment of proteostasis when responding to danger signals that can originate from either outside or within the cell. Proteostasis is primarily governed within a cellular compartment called the endoplasmic reticulum (ER). Despite significant advances in our understanding of the ER, much remains unknown about the molecular basis of proteostasis and how impaired proteostasis can cause cell dysfunction and contribute to human disease. In this project, we discovered patients born with a severely compromised immune system that was caused by inherited mutations that stops their cells from producing a protein that is normally found only within the ER. While very little is known about this protein, our preliminary results led us to believe it contributes to the control of proteostasis, specifically in immune cells. We plan to comprehensively study the blood immune cells from these patients to discover the real function(s) of this molecule in proteostasis control in both the healthy setting and ways by which its deficiency impacts human immunity. To date, our findings show that B cells, a type of immune cell that produces antibodies key circulating molecules that provide immune protection, are particularly sensitive to impaired proteostasis greatly reducing their cellular survival. Furthermore, in another important immune cell, T cells, the loss of proteostasis control caused these cells to act fatigued which was linked to a lowered metabolic capacity. We will delve deeper into understanding proteostasis control in the human immune system by applying a range of sensitive newly developed tools to study proteostasis and ER biology and combine with modern state-of-the-art facilities to provide clues about altered metabolic and cellular pathways contributing to the cell dysfunction and propensity for cell death. Cutting-edge molecular techniques will allow us to identify additional molecular partners of potential relevance that might be involved in our patients disease. Lastly, after combining this newly formed data, with existing currently available information, we will apply computational modelling to predict further candidate proteins whose dysfunction might also cause a similarly damaging immunodeficiency disease. We expect that this project will undoubtedly further our understanding about proteostasis control in the human immune system and uncover important reciprocal links with cellular metabolism.

Research institution(s)
  • St. Anna Kinderkrebsforschung GmbH - 100%
Project participants
  • Thomas Hannich, CeMM – Forschungszentrum für Molekulare Medizin GmbH , national collaboration partner
  • Johannes B. Huppa, Charité - Universitätsmedizin Berlin , national collaboration partner
International project participants
  • Yuning Hong, La Trobe University - Australia
  • Rafael Argüello, CNRS de Marseille-Luminy - France
  • Johannes B. Huppa, Charité - Universitätsmedizin Berlin - Germany

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+43 1 505 67 40

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