The purpose of this resource grant is to function as a core to maintain and create dogs with hemophilia A, hemophilia B, and von Willebrand disease (WVD) for collaborations with other investigators. Our objectives are: 1) To maintain a breeding colony of well-characterized dogs with genetically-determined 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;and 3) To provide specialized support services for research projects using these dogs including canine blood banking and coagulation analyses. These dogs, identified by Dr. Kenneth M. Brinkhous, model human hemophilias and VWD and have been maintained for >50 years at UNC largely through NIH support. Research using the FOBRL dogs has more than doubled during the past 20 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 successfully translated into clinical therapeutics. Thus many advisory boards recommend these dogs as essential for preclinical testing of new treatments for the hemophilias, VWD, and hemorrhage. Major accomplishments during the past 5 years include 24 peer-reviewed publications, over 36 abstract presentations, and obtaining funding separate from but leveraged by this grant that built new, dedicated hemophilia and VWD dog housing. A highly trained staff at the FOBRL has several years of experience in maintaining these special dogs with a dedicated canine blood bank, developing canine coagulation assays, conducting investigations, and collaborating successfully with investigators worldwide. Current research addresses several unmet national needs that include testing new treatments for bleeding, developing a new strain of 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 using these valuable bleeder dogs would be very difficult and expensive to initiate and the survival of this colony would be jeopardized. The cost of establishing a colony at each investigator's institution is prohibitive. This Resource Grant is essential to ensure the survival of the 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 #
5R24HL063098-14
Application #
8286377
Study Section
Special Emphasis Panel (ZHL1-CSR-N (M1))
Program Officer
Link, Rebecca P
Project Start
2008-09-15
Project End
2013-07-31
Budget Start
2012-07-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$722,913
Indirect Cost
$232,869
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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