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Molecular mechanisms involved in the IGF 1R signalling setting of the somatotrop...

Molecular mechanisms involved in the IGF 1R signalling setting of the somatotropic axis This proposal aims to understand molecular mechanisms involved in the induction and persistence of the somatotropic function decrease observed in mice with diminished IGF-I signalling. This alteration could be induced by a specifi... ver más

31/12/2011

INSERM

174K€

Presupuesto del proyecto: 174K€

Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2011-12-31 No tenemos la información de la convocatoria

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Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 174K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto This proposal aims to understand molecular mechanisms involved in the induction and persistence of the somatotropic function decrease observed in mice with diminished IGF-I signalling. This alteration could be induced by a specific heterozygous IGF-1R invalidation in mice brain, and in wild type mice, by a nutrient restriction during the first two weeks of life. Previous results obtained in these both models indicate that diminished IGF-I signalling first decreases hypothalamic GHRH gene expression in first 10 days of life, which alters development of somatotrophs cells in pituitary. Preliminary data indicate that this is not associated with a decrease of GHRH neurons number and suggest an alteration of gene transcription. Environmental programming of endocrine axis activity through gene transcription suggests implication of epigenetic mechanisms. Thus, using the two mice models cited above, I plan to study epigenetic modifications on the GHRH promoter (CpG methylation & histones modifications). GHRH gene expression requires Ikaros that has been shown to act through changes of chromatin access. If modifications of GHRH promoter were confirmed, I will determine Ikaros gene expression by real time PCR. Next, it could be interesting to study Ikaros promoter methylation profile, since it contain 1kb CpG island. The second part of this proposal will be on mechanism involved in the persistence of somatotropic axis decrease and will focus on somatotroph cells, which are a key element of this axis. The study the GH promoter methylation profile will indicate if the gene expression alteration is associated with epigenetic changes. In this case, a particular attention will be hold to its two essentials enhancers, Ikaros and Pit-1. High throughput pyrosequencing will be use to perform these experiments. Latter, questions concerning alteration of somatotrophs proliferation/ differentiation could be raised with a widescreen MDIP array technology present at the Douglass Institute.

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