Canine models of hereditary human diseases are widely used throughout the biomedical community, particularly when no suitable rodent model exists. For both dominant and recessive inherited diseases, affected homozygote animals are normally required for study. In several models, the homozygote dogs die prior to puberty, or have substantially reduced fertility. Breedings between two heterozygotes will result in only 25% of the offspring having the homozygote genotype. Dogs and other larger species have significantly lower litter sizes than rodents and per diem costs up to 20 times that of rodents. These high costs and low levels of production are a major hindrance to research when large numbers of heterozygote breeders are required to produce the necessary number of homozygote pups. The work proposed in this application focuses on the use of transplants of testes or ovaries of prepubertal homozygote dogs into normal littermates as a means of producing clinically healthy animals that can be bred but can also pass on the genes of an affected homozygote. Successful testes and ovary transplants will allow a reduction in the size of the breeding colony, decrease per diem costs and animal housing space requirements, eliminate the production of excess normal animals, and result in increased production of affected animals.
Specific aims i nclude examining the role of dog leukocyte antigen (DLA) haplotype in determining the success of homologous transplantation of prepubertal testes and ovaries when there is at least a partial identity match. The investigators will also determine if prepubertal gonad transplants maintain continued fertility, the ability to sire or deliver healthy pups, and normal hormone levels for at least four years after puberty. This proposal meets National Center for Research Resources (NCRR) objectives of advancing biotechnology and refining animal models. The need for this technology in the biomedical community is evidenced by the seven canine models of hereditary disease where affected animals cannot be used for breeding. These models are currently utilized in 16 individual National Institutes of Health (NIH) grants spanning five different NIH Institutes and Centers (NCRR, NIDDK, NHLBI, NINDS, and NICHD).
| Pullium, J K; Milner, R; Tuma, G A et al. (2008) Fertility after homologous prepubertal testis transplantation in the dog. Transplant Proc 40:2744-9 |
