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Contenu archivé le 2022-12-23

Selective silencing of leukemia-related genes by chemically modified siRNA and shRNA-expressing constructs with improved cell penetration properties

Objectif

The collaborating laboratories will develop new methods for the selective inactivation of leukemia-related genes AML1/ETO, AML1, Lmo2, Evi1 and c-kit. Two strategies for gene silencing will be used to target these genes: 1) chemically-modified nuclease-resistant siRNA with optimized thermodynamic properties and 2) shRNA-expressing cassettes. New synthetic methods for the attachment of chemical groups of different nature to siRNA and DNA fragments for their cellular uptake facilitation will be developed. These methods will include conjugation of siRNA and primers for preparation of expression cassettes to cell-penetrating molecules and post-synthetic conjugation based on original chemistry applicable for screening of a library of ligands.

Cellular uptake and silencing activity of these conjugates will be tested in a model dual fluorescence system, then the most active conjugates will be studied in early hematopoietic progenitor cells, transduced with retroviral constructs that express the target genes, and in bone marrow cells of transgenic mice. These studies will provide an insight into the mechanism of transformation of hematopoietic precursor cells as a result of aberrant expression of gene ensemble and will result in identification of potential markers for differential diagnostics and targets for personalized therapy.

The following benefits are expected to be obtained as a result of this research:
- Development of new chemical strategies for conjugation of oligoribo- and oligodeoxyribonucleotides with various cell-penetrating molecules, including peptides that are compatible with screening of libraries of ligands.
- Development of an efficient unified strategy for correction of gene expression based on the chemically modified RNA and DNA molecules with improved cell uptake properties.
- Design of selective inhibitors of leukemia-related genes and validation of the potential targets for anti-leukemia therapeutics.
- Identification of critical interactions in leukemia-related genes and elucidation of the mechanisms and functional consequences of selective silencing of candidate genes for restoration of differentiation ability of leukemia cells and their reversion to the normal phenotype.

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Appel à propositions

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Régime de financement

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Coordinateur

UNIVERSITÄT HAMBURG
Contribution de l’UE
Aucune donnée
Adresse
MARTINY STRASSE, 52
HAMBURG
Allemagne

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Coût total
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Participants (3)