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. Programa(s) IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993- Tema(s) OPEN - OPEN Call Convocatoria de propuestas Data not available Régimen de financiación Data not available Coordinador Muséum National d'Histoire Naturelle Aportación de la UE Sin datos Dirección rue Cuvier 43 75231 Paris Cedex 05 Francia Ver en el mapa Enlaces Sitio web Opens in new window Coste total Sin datos Participantes (4) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo CNRS - Université Pierre et Marie Curie Paris 6 Francia Aportación de la UE Sin datos Dirección place Jussieu 4 75252 Paris Cedex 05 Ver en el mapa Coste total Sin datos M. V. Lomonosov Moscow State University Rusia Aportación de la UE Sin datos Dirección Leninskie gory 119992 Moscow Ver en el mapa Coste total Sin datos Siberian Branch of Russian Academy of Sciences Novosibirsk Institute of Bioorganic Chemistry Rusia Aportación de la UE Sin datos Dirección Lavrentyev prospekt 8 630090 Novosibirsk Ver en el mapa Coste total Sin datos University of Southern Denmark Dinamarca Aportación de la UE Sin datos Dirección Campusvej 55 5230 Odense M Ver en el mapa Coste total Sin datos