The overall objective of this project is for the Referral Center for Animal Models of Human Genetic Disease (RCAM) to continue to serve as a national referral and resource center to discover, characterize, and maintain colonies of large animals with hereditary diseases homologous to those found in human patients that can be used to translate preclinical trials from kennel to clinic. The naturally occurring animal models to be sought, and those currently available, represent true orthologs of their respective human disease, involving defects in the same genes and resulting in the same molecular, biochemical, pathological, and clinical signs as in human patients. While numerous naturally occurring models of disease have been identified and proven critical for preclinical trials, the rate at which new mutations are found and characterized is limited. Therefore, we will now also create feline models that bear the same genetic mutation as those found in human diseases using CRISPR/Cas9 genome editing. These animal models can be generated quickly, will be completely orthologous to the human system, and will be maintained in breeding colonies and disseminated to other investigators. Both newly discovered and generated models are invaluable for the study of disease pathogenesis and the evaluation of the safety and efficacy of therapies prior to clinical trials in human patients. Models offering new opportunities to investigate disease pathogenesis and approaches to therapy will be emphasized in consultation with an Advisory Committee. Verified models will be made available to other investigators at a nominal fee-for-service in the form of DNA, cells, frozen semen, and breeding stock. We will also serve as a resource for normal large animals and their tissues for other investigators, and we will continue to offer facilities where outside investigators can perform experiments in large animal models on a Program Income Fund, fee-for-service basis.

Public Health Relevance

? OVERALL COMPONENT The Referral Center discovers, characterizes, and maintains colonies of large animals (dogs and cats) with hereditary diseases homologous to those found in human patients for the study of disease pathogenesis and to develop effective and safe therapies for human patients.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Material Resource Grants (P40)
Project #
2P40OD010939-34A1
Application #
9633111
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zou, Sige
Project Start
1985-09-20
Project End
2023-12-31
Budget Start
2019-01-18
Budget End
2019-12-31
Support Year
34
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Inal-Gültekin, Güldal; Topta?-Hekimo?lu, Bahar; Görmez, Zeliha et al. (2017) Myophosphorylase (PYGM) mutations determined by next generation sequencing in a cohort from Turkey with McArdle disease. Neuromuscul Disord 27:997-1008
Bauer Jr, Thomas R; Pratt, Suzanne M; Palena, Christina M et al. (2017) Feline leukocyte adhesion (CD18) deficiency caused by a deletion in the integrin ?2 (ITGB2) gene. Vet Clin Pathol 46:391-400
Casal, Margret L; Wang, Ping; Mauldin, Elizabeth A et al. (2017) A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs. PLoS One 12:e0170708
Szelecsenyi, Arlette Cornelia; Giger, Urs; Golini, Lorenzo et al. (2017) Survival in 76 cats with epilepsy of unknown cause: a retrospective study. Vet Rec 181:479
Hilton, Stephanie; Mizukami, Keijiro; Giger, Urs (2017) [Cystinuria caused by a SLC7A9 missense mutation in Siamese-crossbred littermates in Germany]. Tierarztl Prax Ausg K Kleintiere Heimtiere 45:265-272
Yabuki, Akira; Iwanaga, Tomoko; Giger, Urs et al. (2017) Acquired Fanconi syndrome in two dogs following long-term consumption of pet jerky treats in Japan: case report. J Vet Med Sci 79:818-821
Mauldin, Elizabeth A; Wang, Ping; Olivry, Thierry et al. (2017) Epidermolysis bullosa simplex in sibling Eurasier dogs is caused by a PLEC non-sense variant. Vet Dermatol 28:10-e3
Shao, Hongguang; Li, Xinshe; Lok, James B (2017) Heritable genetic transformation of Strongyloides stercoralis by microinjection of plasmid DNA constructs into the male germline. Int J Parasitol 47:511-515
Lynch, Michael; McGrath, Ken; Raj, Karthik et al. (2017) HEREDITARY FACTOR VII DEFICIENCY IN THE ASIAN ELEPHANT (ELEPHAS MAXIMUS) CAUSED BY A F7 MISSENSE MUTATION. J Wildl Dis 53:248-257

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