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Contenido archivado el 2022-12-23

Inhibition of the Insulin-like Growth Factor I Expression by Targeting its Gene or Messenger RNA

Objetivo

The objective of this project is suppression of the insulin-like growth factor I (IGF-I) or its receptor (IGF-IR) biosynthesis by targeting their messenger RNA with synthetic nucleic acids. The principal emphasis will be done on the recent and most perspective strategy of small interfering RNA (siRNA) and deoxyribozymes (DNAzymes). In order to increase stability and penetration of the RNA oligomers into cells different modification of RNA backbones and eventually bases will be done and effect of these modifications on synthetic nucleic acid reagent efficacy will be studied.

siRNA and deoxyribozyme action will be compared to that of other inhibitors such as antisense oligonucleotides, antisense RNA (targeting mRNA) or triple helix-forming oligonucleotides (targeting directly genomic double-stranded DNA). The most effective inhibitor will be selected in these comparative researches.

Then the interaction of these inhibitors with living cells in culture will be studied. We propose to attach to these agents different chemically or biologically active or fluorescent molecules for studies of their penetration and intracellular behavior. Synthetic peptides will be used to facilitate penetration of the oligonucleotides into cells, as well as to address the inhibitor either to cytoplasm, or to nucleus and other subcellular structures.

In order to achieve the objectives of the project the following studies will be undertaken:
- Chemical synthesis of small double-stranded RNA and deoxyribozymes with natural backbone and with substitutions by modified nucleotides (2'-O-methyl or LNA) and shortened ribozymes with modified oligonucleotide effectors.
- Synthesis of antisense and triple helix-forming oligonucleotides as well as their fluorescent conjugates and molecular beacons.
- Design and synthesis of peptides facilitating penetration of nucleic acids inside the cells and improving their intracellular distribution.
- Synthesis of conjugates between modified nucleic acid-based reagents and penetration peptides or molecules stabilizing complex formation with the targets.
- Studies of penetration of these conjugates into the living cells by fluorescent or confocal microscopy.
- Studies of effects of these synthetic inhibitors on the IGF-I and IGF-IR gene expression in cell cultures.
Expected output of the project is to obtain new potent sequence specific synthetic molecules capable to knockdown the expression of IGF-I or its receptor in order to inhibit the oncogenic transformation processes and potentially to cure the development of certain tumors. The results of the research may have a great impact not only into fundamental studies of cancerogenesis, but also into potential anti-cancer therapeutical applications based on artificial regulation of gene expression.

Convocatoria de propuestas

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Régimen de financiación

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Coordinador

Muséum National d'Histoire Naturelle
Aportación de la UE
Sin datos
Dirección
rue Cuvier 43
75231 Paris Cedex 05
Francia

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Enlaces
Coste total
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Participantes (4)