Descrizione del progetto
Infiammazione cronica: può portare alla leucemia?
Prove emergenti suggeriscono che il microambiente del midollo osseo potrebbe svolgere un ruolo attivo nello sviluppo di neoplasie ematologiche. In particolare, l’infiammazione cronica genera mediatori chiave che possono influenzare le cellule staminali ematopoietiche (HSC, haematopoietic stem cell), portando all’esaurimento della capacità di auto-rinnovamento e persino alla leucemia. Gli scienziati del progetto SuccHSC, finanziato dall’UE, si propongono di studiare il ruolo del succinato, una delle principali molecole effettrici indotte dall’infiammazione, che può raggiungere il nucleo e modificare gli istoni. I ricercatori studieranno l’impatto del succinato sulla modificazione dell’istone e sull’espressione genica in campioni normali e leucemici, fornendo informazioni sullo sviluppo della leucemia.
Obiettivo
In life, no matter how small, changes can have huge impact on its quality. For hematopoietic stem cells (HSC), similar can happen. Through minor shifts, from normal to pre-leukemic and finally leukemic phenotype, generation of leukemic stem cells (LSC) results in overt malignancy, such is acute myeloid leukemia (AML). Life quality of AML patients is severely impaired, even in “disease-free” state after the treatment. AML chemotherapy and stem cell transplant offers 5-year survival to only 20% of patients above age of sixty, 40% to the rest. Currently, a major clinical factor in AML onset and relapse are ever-present LSC. Mechanisms by which HSC turn into LSC, in their highly regulated environment, are still largely unknown, which is why new knowledge is needed to unveil this troubling issue. With the growing amount of data correlating chronic inflammation and onset of various types of malignancies, the SuccHSC project will explore the role of succinate, one of the major inflammation-induced effector molecules, in LSC formation by epigenetic remodeling of HSC. Chronic inflammation generates various molecules, which can be picked-up by bone marrow HSC. Chronic HSC activation leads to peripheral blood entering, myeloid skewing, self-renewal exaustion and even perhaps leukemia. On mechanistic side, HSC react to inflammatory mediators by elevated glycolysis, reduced oxygen and increased succinate. New succinate molecules can reach nucleus through mito-nuclear communication. Among other modifications, histones were shown to be modified with succinate, but yet with no known role. SuccHSC will explore histone succinylation and its effect on gene expression comparing leukemic and normal human samples biochemically, by ChIP-seq and by RNA-seq. Transgene succinate-dehydrogenase KO mice model, which accumulates succinate, will be used to confirm succinylation role in gene expression regulation and HSC transformation into pre-leukemic cell stage.
Campo scientifico (EuroSciVoc)
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP.
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP.
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Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
9019 Tromso
Norvegia