Descrizione del progetto
Meccanismi di omeostasi proteica durante l’invecchiamento
Le proteine sono fondamentali per tutti i processi biologici ma sono soggette a disfunzioni, aggregazioni e danni, soprattutto con l’invecchiamento delle cellule. I meccanismi di proteostasi, come quelli che coinvolgono i chaperoni e i sistemi proteolitici come il proteasoma, lavorano insieme per monitorare la qualità delle proteine e riparare o rimuovere quelle danneggiate o mal ripiegate. Il progetto StemProteostasis, finanziato dal Consiglio europeo della ricerca, si concentra sul ruolo del proteasoma nella funzione delle cellule staminali embrionali umane (hESC). I ricercatori studieranno le diverse vie della proteostasi nelle hESC e nelle cellule somatiche per capire come influiscono sull’esaurimento delle cellule staminali e sulla degenerazione dei tessuti. I risultati del progetto forniranno inoltre importanti informazioni sul ruolo della proteostasi nell’invecchiamento e nelle malattie legate all’età.
Obiettivo
By 2050, the global population over the age of 80 will triple. Thus, research for improving the quality of life at older age can be of enormous benefit for our ever-aging society. To address this challenge we propose an innovative approach based on a combination of stem cell research with genetic experiments in C. elegans. Mechanisms that promote protein homeostasis (proteostasis) slow down aging and decrease the incidence of age-related diseases. Since human embryonic stem cells (hESCs) replicate continuously in the absence of senescence, we hypothesize that they can provide a novel paradigm to study proteostasis and its demise in aging. We have found that hESCs exhibit increased proteasome activity. Moreover, we have uncovered that the proteasome subunit RPN-6 is required for this activity and sufficient to extend healtshpan in C. elegans. However, the mechanisms by which the proteasome regulates hESC function remain unknown. Our first aim is to define how the proteasome regulates not only hESC identity but also aging and the onset of age-related diseases. Moreover, one of the next challenges is to define how other proteostasis pathways impinge upon hESC function. We hypothesize that, in addition to the proteasome, hESCs differentially regulate other subcellular stress response pathways designed to protect them from disequilibrium in the folding and degradation of their proteome. We will perform a comprehensive study of proteostasis of hESCs and mimic this network in somatic cells to alleviate age-related diseases. Finally, we will determine whether loss of proteostasis promotes somatic stem cell (SC) exhaustion, which is one of the most obvious characteristics of the aging process and contributes to tissue degeneration. By using mouse models we will examine whether sustained proteostasis delays neural SC exhaustion. Our research will have an impact in several fields such as stem cell research, neurogenesis, proteostasis, aging and age-related diseases.
Campo scientifico
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding
- medical and health sciencesbasic medicinephysiologyhomeostasis
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
50931 Koln
Germania