Pilot & Feasibility Funding Programs
Pilot & Feasibility Program Application Abstract
An outbred mouse strain to study diabetic nephropathy
Raymond Harris (Nashville, TN)
To date, the AMDCC has nearly exclusively characterized inbred laboratory mice strains to study the development diabetes nephropathy. These studies support the influence of genetic risk factors as contributing to diabetic nephropathy in these inbred lines. In this regard some strains, like DBA2 develop more robust nephropathy than C57BL/6. Nevertheless, the complexity the genomes of inbred mouse strain are drastically reduced, as compared to the genetic complexity of outbred human populations. Inbred mice are homozygous at all loci; whereas in outbred populations, loci allowed to exist in both heterozygous and homozygous states . Furthermore during the process of brother-sister mating used to derive inbred mouse strains, any polymorphisms that either decrease fecundity or are lethal when homozygous, are lost. If similar mutations contribute, in a dominant or semi-dominant fashion, to human diabetic nephropathy, this variability would never be seen in inbred mouse models. In this regard, one of the specific suggestions of the AMDCC External Advisory Committee was to consider utilizing outbred mouse strains to investigate genetic predisposition for development of diabetic complications. We propose to characterize the progression of nephropathy in diabetic outbred CD-1 mice. A recent study has reported that CD-1 mice develop significant nephropathy in a streptozotocin-induced model of diabetes. This study reported that mice made diabetic by a high dose (single injection) streptozotocin protocol develop ESRD associated with prominent tubulointerstitial nephritis and fibrosis within 3 months and die because of diabetic complications by 6-7 months. In this regard, our own preliminary data in CD-1 mice indicate significant diversity in the levels of albuminuria (following STZ induced diabetes) among individual mice (see below). Such heterogeneity may indicate that outbred mice might more closely resemble the heterogeneity of human populations and might also provide the opportunity to capture dominant genes that contribute to increased albuminuria and diabetic nephropathy. For this reason, we propose to characterize the extent and heterogeneity of diabetic nephropathy in CD-1 mice and to begin to develop crosses for detecting dominant heritable traits predisposing to development and/or progression of diabetic nephropathy. Our first specific aim will be to characterize the variability of the development of nephropathy in the CD-1 strain. Our second specific aim is to to initiate a backcross of CD-1 mice with B6Akita mice, a strain resistant to development of diabetic nephropathy, in order to begin to identify potential dominant alleles that contribute to diabetic nephropathy.