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

Projektinformationen

INTAS 2006-1000013-9117

ID Finanzhilfevereinbarung: INTAS2006-1000013-9117

Startdatum 1 Februar 2007

Enddatum 31 Januar 2009

Finanziert unter

• International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Gesamtkosten € 75 000,00

EU-Beitrag € 150 000,00

Koordiniert durch

UNIVERSITÄT HAMBURG
Germany

Ziel

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.

Schlüsselbegriffe

• Biochemistry
• Experimental & Clinical Oncology
• Nucleic Acids

Programm/Programme

• IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Thema/Themen

Data not available

Aufforderung zur Vorschlagseinreichung

Data not available

Finanzierungsplan

Data not available

Koordinator

UNIVERSITÄT HAMBURG

• EU-Beitrag: Keine Daten
• Adresse: MARTINY STRASSE, 52 ; HAMBURG ; Deutschland
• Gesamtkosten: Keine Daten

Beteiligte (3)

ENGELHARDT INSTITUTE OF MOLECULAR BIOLOGY

Russland

• EU-Beitrag: Keine Daten
• Adresse: VAVILOV STREET, 32 ; MOSCOW
• Gesamtkosten: Keine Daten

INSTITUTE OF CHEMICAL BIOLOGY AND FUNDAMENTAL MEDICINE

Russland

• EU-Beitrag: Keine Daten
• Adresse: PROSPEKT AKAD. LAVRENTIEVA, 8 ; NOVOSIBIRSK
• Gesamtkosten: Keine Daten

UNIVERSITY OF SURREY

Vereinigtes Königreich

• EU-Beitrag: Keine Daten
• Adresse: STAG HILL ; GUILDFORD
• Gesamtkosten: Keine Daten