MISS-SA

Molecular mechanisms involved in the IGF-1R signalling setting of the somatotropic axis

Coordinatore	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)    more  Organization address address: 101 Rue de Tolbiac city: PARIS postcode: 75654 contact info Titolo: Ms. Nome: Mihaja Cognome: Auguste Email: send email Telefono: +33 148 073 415 Fax: +33 148 073 432
Nazionalità Coordinatore	France [FR]
Totale costo	173˙509 €
EC contributo	173˙509 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-IOF-2008
Funding Scheme	MC-IOF
Anno di inizio	2009
Periodo (anno-mese-giorno)	2009-09-01   -   2011-12-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)  Organization address address: 101 Rue de Tolbiac city: PARIS postcode: 75654 contact info Titolo: Ms. Nome: Mihaja Cognome: Auguste Email: send email Telefono: +33 148 073 415 Fax: +33 148 073 432	FR (PARIS)	coordinator	173˙509.69

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 Obiettivo del progetto (Objective)

'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.'