Ziel
While mutations at protein-coding sequences have been extensively characterized, the functional role of disease-associated non-coding variants remains largely elusive. In fact, germline non-coding variants are often associated with increased risk of childhood cancers. In B-cell derived acute lymphoblastic leukemia (B-ALL), the most common type of cancer in children, non-coding sequence variation at lineage-specific genes, such as IKZF1, GATA3 and CEBPE is associated with disease. Interestingly, the strongest risk factor maps at ARID5B, a DNA-binding protein described to promote the removal of repressive histone marks. Still, the role of ARID5B in leukemia and haematopoiesis remains largely uncharacterized. Thus, we hypothesize that non-coding variants associated with B-ALL affect the activity of distal regulatory elements, modulating the expression of ARID5B and other B-cell lineage-specific genes (objective 1). We further postulate that ARID5B promotes the de-repression of lineage-specific genes (objective 2), playing a crucial role in B-cell development and B-ALL initiation and progression (objective 3). To test these hypotheses, I will develop a novel CRISPR screen approach to dissect ARID5B enhancers at single nucleotide resolution (work package 1). I will use a combination of genomics and transcriptomics methods after acute and prolonged degradation of ARID5B to elucidate the molecular function of ARID5B in B-ALL (work package 2). Finally, I will use mouse models and focus on the physiological relevance of ARID5B in B-cell development and leukemia initiation and progression, in vivo. (work package 3). Together, I will dissect the role of non-coding variants at leukemia-associated loci, characterize the molecular function of ARID5B and elucidate the pathophysiological relevance of ARID5B.
Wissenschaftliches Gebiet (EuroSciVoc)
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht.
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht.
- NaturwissenschaftenBiowissenschaftenBiochemieBiomoleküleProteine
- NaturwissenschaftenBiowissenschaftenGenetikMutation
- Medizin- und GesundheitswissenschaftenKlinische MedizinOnkologieLeukämie
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Schlüsselbegriffe
Programm/Programme
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsKoordinator
1090 Wien
Österreich