The purpose of this resource grant is to maintain and create dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and FVII deficiency for independent and collaborative research. Our objectives are: 1) To maintain a breeding colony of well-characterized dogs with inherited bleeding disorders at the Francis Owen Blood Research Laboratory (FOBRL), University of North Carolina, Chapel Hill;2) To produce purpose-bred, affordable research animals with these bleeding disorders in a cost effective manner;3) To provide specialized support services for research projects using these dogs including canine blood banking and coagulation analyses, and 4) To acquire and characterize new canine models of inherited bleeding disorders. These dogs, identified by Dr. Kenneth M. Brinkhous, model human hemophilias and VWD and have been maintained for >60 years at UNC largely through NIH support. Research using the FOBRL dogs has more than doubled during the past 30 years and has led to discoveries that have revolutionized the treatment of inherited and acquired bleeding and thrombotic disorders. Many therapeutic agents were developed and tested in these dogs and then successfully translated into the clinic. Thus many advisory boards recommend these dogs as essential for pre-clinical testing of new treatments for these inherited bleeding disorders. Major accomplishments during the past 5 years include 37 peer-reviewed publications while building new and completely renovating existing animal facilities. A highly trained staff at the FOBRL has years of experience maintaining these dogs with a dedicated canine blood bank, developing canine coagulation assays, conducting investigations, and collaborating successfully with investigators worldwide. Current research includes in vivo validation of new treatments for bleeding, developing hemophilia A dogs with inhibitors, and determining the acute and chronic sequelae of gene therapy on genetic diseases. This grant is the only support for maintenance of this colony. Without this grant, new research would be very difficult and expensive to initiate and the survival of this colony would be jeopardized. This Resource Grant is essential to assure the survival of this colony in an established, successful environment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Resource-Related Research Projects (R24)
Project #
5R24HL063098-16
Application #
8712535
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M2))
Program Officer
Link, Rebecca P
Project Start
1999-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
16
Fiscal Year
2014
Total Cost
$1,048,483
Indirect Cost
$357,183
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Marcos-Contreras, Oscar A; Smith, Shannon M; Bellinger, Dwight A et al. (2016) Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII. Blood 127:565-71
Siner, Joshua I; Samelson-Jones, Benjamin J; Crudele, Julie M et al. (2016) Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models. JCI Insight 1:e89371
Shetty, Krithika A; Merricks, Elizabeth P; Raymer, Robin et al. (2016) Soy Phosphatidylinositol-Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain-Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs. J Pharm Sci 105:2459-64
Lozier, Jay N; Kloos, Mark T; Merricks, Elizabeth P et al. (2016) Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII. Comp Med 66:405-411
Nichols, Timothy C; Whitford, Margaret H; Arruda, Valder R et al. (2015) Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs. Hum Gene Ther Clin Dev 26:5-14
Kidd, L; Geddings, J; Hisada, Y et al. (2015) Procoagulant microparticles in dogs with immune-mediated hemolytic anemia. J Vet Intern Med 29:908-16
Sauna, Zuben E; Lozier, Jay N; Kasper, Carol K et al. (2015) The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics. Blood 125:223-8
Cantore, Alessio; Ranzani, Marco; Bartholomae, Cynthia C et al. (2015) Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med 7:277ra28
Nichols, Timothy C (2014) Lessons Learned from Animal Models of Inherited Bleeding Disorders. Hematol Educ 8:39-46
Sherman, Alexandra; Schlachterman, Alexander; Cooper, Mario et al. (2014) Portal vein delivery of viral vectors for gene therapy for hemophilia. Methods Mol Biol 1114:413-26

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