Previous work of our project focused on the identification of gene-diet interactions of complex traits in mice with a focus on inflammatory phenotypes, such as anti-nuclear antibodies (ANA). For this, a large colony of outbred, autoimmune-prone mice (AIL) were fed on three different diets, and subject to deep phenotying. Based on quantitative trait loci (QTL) mapping, full-genome sequencing of AIL parental mice and RNA-sequencing of the spleens, we identified mutations of Tnxb as a diet-regulated polymorphisms to promote ANA production. These mutations within Tnxb seem to be of functional importance because, the polymorphism (i) was only present in progeny of lupus-prone NZM2410 mice gene expression, (ii) is driven by diet and (iii) low Tnxb expression was associated with lupus nephritis in NZM2410 mice.
Mutations of Tnxb emerged as potential risk for the development of ANA and lupus nephritis. These mutations were only observed in progeny of lupus-prone NZM2410 mice, but not of the other three parental strains. Hence, we here will evaluate the functional relevance of this mutation by generating NZM2410 mice with the “wild type” genome and vice versa.
We will edit the mutation within the Tnxb gene in NZM2410 mice to the one observed in the other three parental strains of AIL mice using CRISPR/Cas (commercial supplier). Furthermore, the “wild type” mutation of Tnxb will be introduced into NZM2410 mice using the same technique. All mouse strains will then be exposed to calorie restricted, control and western diet. The primary endpoint of this study is the prevalence of ANA and proteinuria. Secondary endpoints include longitudional immunophenotyping as well as investigation of the gut microbiome.
Requirements for the position:
MB degree in natural science.