Mouse genetics and phenotyping

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Mouse Genetics and Phenotyping to derive Models of Diabetes and Kidney Diseases

Functional genome analysis relies on the availability of allelic series of genes in model organisms. The establishment of animal models for human diseases contributes to the identification of the causes and the pathogenesis as well as to the development of strategies for the treatment of the diseases. Thus, biomedical research with mice includes the search for as well as the analysis of alleles predisposing for or protecting against specific diseases. A strategy for the search of novel disease-related alleles is the random chemical mutagenesis of a large number of animals followed by systematic screening for clinically relevant disease phenotypes. A widely used mutagen is N-ethyl-N-nitrosourea (ENU) which predominantly induces point mutations. In the phenotype-driven Munich ENU mouse mutagenesis project, offspring of the mutagenized animals were examined for mutations in various phenotypic screens by using appropriate routine procedures allowing the examination of large numbers of mice for a broad spectrum of parameters. Affected mice were tested for the transmission of the altered phenotype to the subsequent generations followed by the identification of the mutation causing the heritable aberrant phenotype and the further in-depth analysis of the mutant lines. ENU-induced mice with the causative mutation already identified are successfully used in different areas of biomedical research. In the clinical chemical (substrates, proteins, electrolytes, enzyme activities) and hematological screen, we established a large number of mutant lines harboring a dominant or recessive mutation with heritable defect in specific blood parameters. Cryopreserved sperm is available for the re-derivation of these lines. Our work especially focuses on the generation and functional analysis of mutant lines exhibiting increased blood glucose values or increased blood urea values for the establishment of novel appropriate animal models for human diabetes or nephropathy, respectively. Here we use morphological, patho-histological, molecular genetic as well as clinical and functional analyses. In addition, we carry out the clinical chemical and hematological screen within the German Mouse Clinic (GMC) at the Helmholtz Center Munich thereby contributing to the systematic phenotypic characterization of mouse models derived from other phenotype-driven or genotype-driven projects.