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Abstract

Grant Number:	2P01HD024605-11A10002
Project Title:	MOUSE MODELS FOR DOWN SYNDROME

PI Information:	Name	Email	Title
	REEVES, ROGER H.	rreeves@jhmi.edu	PROFESSOR

Abstract: The overall goal of this research program is to correlate specific genes with specific phenotypes of DS. In the next project period, we will continue to refine and characterize mouse models to study the etiology of developmental anomalies that occur in Down Syndrome (DS). The proposed experiments will create mice with a genetic insult more similar to that in DS by chromosomal engineering to create a duplication/deletion in the mouse Chr10 region of conserved linkage with human Chr 21 (Hc21). Contributions of genes in this region to developmental anomalies seen in DS will be characterized by assessing a variety of phenotypes within this project and through the Cores. Normal functions of gene in the Chr10 segment will be evaluated by targeted saturation mutagenesis across the engineered deletion. In addition to identifying roles of these genes in normal processes in development, this approach can create mutations corresponding to a variety of diseases mapping to this region, as well. Genome wide changes in expression will be addressed by comparing patterns of gene expression using RNA (cDNA) from affected tissues of segmental trisomy and control mice to screen expression patterns in arrays comprised of thousands of cDNAs. We will coordinate with Project 2 to validate alternative assays for assessing altered gene expression in the animal models of aneuploidy developed in this program. Cre/lox based chromosome engineering will be used to create segmental trisomy for the region of conserved linkage between HSA21 and Chr10. We recently completed YAC and PAC contigs of the entire segment, identifying 22 genes in this region. More than 3 MB of contiguous template is being sequenced currently, including an evolutionary chromosome junction. PAC transgenic mice will provide localization of genes contributing to specific phenotypes and will be used to complement recessive phenotypes in mutagenized mice. Gene function will be assessed using targeted saturation mutagenesis of the deleted region of mouse Chr10, and by a "sensitization screen" in Ts65Dn mice with segmental trisomy for Chrl6. Gene expression throughout the genome will be assessed using cDNA array technologies to identify pathways disrupted in two target tissues in trisomy, and to identify genes, allelic variants of which contribute to the variable presentation of DS in an outbred population (i.e., human beings). A cerebellar phenotype that we discovered in Ts65Dn mice correctly predicted a corresponding deficit in DS. Dysmorphology of the cranial skeleton corresponding to changes in DS has also been documented. We will continue phenotype assessment in Ts65DN mice and in the new models produced here and extending our observations earlier in development.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
Downs syndrome, developmental genetics, disease /disorder model, gene targeting, growth /development, model design /development, trisomy
gene dosage, genetic mapping
artificial chromosome, laboratory mouse, microarray technology, site directed mutagenesis, transfection, transgenic animal

Institution:	JOHNS HOPKINS UNIVERSITY
	W400 Wyman Park Building
	BALTIMORE, MD 21218
Fiscal Year:	2000
Department:
Project Start:	25-MAY-2000
Project End:	30-NOV-2000
ICD:	EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
IRG:

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