Reference:
2
Abstract:
This project was inspired by a series of preliminary results obtained by the proposer: It has established a unique relationship between mutations in the gene, the severity of the phenotype and the levels of some markers ZO, such as F2 isoprostanes and F4 and iron not bound to protein (NPBI) in plasma of patients RTT. The levels of F2 and F4 isoprostanes and NPBI are markers of lipid peroxidation, which in turn indicates the presence of SO (Esterbauer et al., 1991; Buonocore et al., 2003; Milne et al., 2008). Treatment with long-chain fatty acids, such as docosahexaenoic acid mixture / eicosapentaenoic (EPA-DHA) performed by one of the groups participating in the project (Dr. Y. Hayek, Policlinico Le Scotte, Siena) in 21 patients for 6 months RTT showed significant improvement in clinical parameters evaluated using the stairs Kerr and Percy. The relationship between pathological changes of MECP2 and the level of markers of OS is stored in two recognized animal models for Rett syndrome. In plasma and in the brain of mice null Mecp2 – / y (Guy et al., 2001) and in the brain of the model carrier of a truncating mutation 308 Mecp2-/ y (Shahbazian et al., 2002) the level of F2 and F4 isoprostanes and NPBI is significantly altered. With this project we propose to study the effects, molecular and behavioral administration of the mixture of DHA-EPA in the murine model no. The treatment of patients with DHA-EPA, which will be continued and carried out on a larger number of patients with funding already allocated to the specific group of the General Hospital of Siena, will contribute only in part to the understanding of the mechanism of action of these fatty acids on molecular pathways and behavior. For example, little information can be obtained about the effect of this treatment on the life span of the treated subject, or on the period of onset of symptoms. For this reason, thanks to the experience in the field of behavioral study of one of the groups proposing, we will test whether treatment with DHA-EPA can counteract the behavioral and motor abnormalities previously shown in the mouse model (Ricceri et al., 2008; De Filippis et al., 2010). In parallel, we will make a series of morphological and functional analysis, such as the evaluation of plasma levels of leptin, assessing the level of BDNF in the hippocampus, immunohistochemical analysis of neurons and glial cells at the level of different brain areas, as well as magnetic resonance imaging (MRI ) and spectroscopy (MRS), with or without treatment with DHA-EPA. At the molecular level, will be assessed markers of SO and the level of ROS in different tissues, such as plasma, brain, and lung, tissues easily accessible in the murine model described above, with or without treatment with DHA-EPA. Recently, Rett syndrome has been associated with an alteration in the expression profile of microRNAs (Urdinguio et al., 2010; Wu et al., 2010). In the light of this evidence, will be analyzed the expression profiles of microRNAs by microarray hybridization specific, as is already carried out by the proponent group, for a different pathology chromatin (Gatto et al., 2010). The study will be carried out in the hippocampus, hypothalamus and cerebellum of the mouse model MeCP2-/ y with or without treatment with DHA-EPA. This analysis should show a reversal of microRNA levels following treatment with DHA-EPA.
PROJECT DETAILS
beginning: 2010.
end: 2011.
Country of research: Italy
Counry of funding source: Italy
Funding organization: AIRETT
Financing: PRIVATE FUNDERS – 80 000 €