The main objective of this project is to evaluate the implication of selected genes from HC21 in 1DS. The study is based on the development and study of different types of transgenic mice that overexpress one or several genes from HC21 that are believed to be important in D5. The project brings together five European research groups who are working on the characterisation of genes from HC21, on the development of mice transgenic for HC21 genes and on the analysis of a mouse model for DS (Ts65Dn).
Down syndrome (DS) is the most common cause of mental retardation, affecting between 200,000 and 300,000 patients in the European Union. DS results from the overexpression of several human chromosome 21 (HC21) genes that are triplicated in patients with this chromosomal abnormality. Although HC21 contains among 500 and 1000'genes, which are being identified in an international research effort, it is expected that only some of them are of particular importance in producing the main clinical features of DS. After the identification of the HC21 genes the understanding of the pathophysiology of this disorder should be facilitated by the development and functional analyses of animal models that selectively overexpress some of the genes that are triplicated in DS.
The general strategy of the project is to develop different mouse models for the following HC21 genes: MNB, AML1, CBS, GIRK2, PEP19 and EZH2. The selected genes are anticipated to be involved in several of the phenotypic alterations of DS, and were selected based on their location in the chromosomal region that has been considered critical for the development of the syndrome, or due to prior knowledge of the functions of the proteins they encode. The different types of transgenic mice will contain either the genomic region spanned by the gene or the corresponding cDNA driven by a promoter which will overexpress the gene in tissues expected to be affected in DS. Mice transgenic for three other HC21 genes (SIM2 SOD1 and DSCR1), implicated in DS, have already been developed and will be characterized along with- the transgenic mice generated in this project. Transgenic mice that overexpress two or more HC21 genes will be generated by crossing mice transgenic for the single genes. The project also includes the interspecies functional screening of three HC21 genes MNB, SIM2 and GIRK2 by engineering transgenic mice using the Fugu homologues of these genes.
RNA in situ hybridisation, immuno-histochemistry, biochemistry, pathological, morphological and developmental experiments will be performed to evaluate the functions of these genes. The behavioural characteristics of all the transgenic mice generated will be assessed, including the evaluation of developmental and sensorimotor parameters, spontaneous activity, emotionality, and learning and memory, using a battery of experimental tasks, specifically designed for the evaluation of mouse models with possible cognitive impairment, and will be compared with their non-transgenic littermates and the Ts65Dn mice The animal models should help in understanding some of the main clinical alterations observed in DS and might facilitate the development of clinical interventions for early correction of some of the major features of DS.
Down Syndrome; Chromosome 21; Transgenic Mice; Partial Chromosome 21 Trisomy; Mental Retardation; Animal Models.
Fields of science
Call for proposalData not available
Funding SchemeCSC - Cost-sharing contracts
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1211 Genève 4
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