Disorders of blood coagulation and thrombosis complicating atherosclerosis are major causes of death and disability. Our objectives in this Resource Grant are: 1) To maintain a breeding colony of well- characterized dogs with genetically-determined bleeding disorders at the Francisco Owen Blood Research Laboratory (FOBRL), University of North Carolina, Chapel Hill; 2) To produce purpose bred-research animals with these bleeding disorders; and 3) To provide specialized support services for research projects using these dogs including canine blood banking and coagulation analyses. These dogs model human hemophilia A, hemophilia B, and von Willebrand disease (vWD) and have been maintained for over 50 years in Chapel Hill largely through support from the NIH. A well-trained support staff at the FOBRL has several years experience in managing these special dogs, maintaining a canine blood bank, developing and performing canine coagulation assays, conducting investigations, and collaborating successfully with investigators worldwide. As a result, research using the dugs from the FOBRL has lead to discoveries that have revolutionized treatment of inherited and acquired bleeding and thrombotic disorders. Many therapeutic agents have moved successfully from the research bench to clinical practice after being conceived of and tested in these dogs. Current research with these large animal models addresses several unmet national needs including the development of new methods of treatment for bleeding and thrombosis, and determination of the acute and chronic sequelae of these new treatments on genetic diseases. As such, these dogs constitute a unique national resource that have been regarded by many investigators as essential for pre-clinical testing of new treatments for the hemophilias, vWD, arterial thrombotic disorders, and hemorrhage. The demand for and use of these hemophilic dogs has nearly doubled during the past two decades. Beginning March 1999, there will be no NIH grant support for the maintenance of this colony making new research using these priceless bleeder drugs very difficult and extensive to initiate. The survival of the FOBRL colony will be jeopardized. The cost of establishing a colony at each investigator's institution is prohibitive. The primary benefit of this grant will be to maintain breeding stock for producing affordable, purpose-bred research animals in a cost-effective manner for the research community. The research animals will be supported by mechanisms that will separate from this Resource Grant. This Resource Grant is essential to ensue 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 #
5R24HL063098-02
Application #
6184748
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$548,879
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
French, Robert A; Samelson-Jones, Benjamin J; Niemeyer, Glenn P et al. (2018) Complete correction of hemophilia B phenotype by FIX-Padua skeletal muscle gene therapy in an inhibitor-prone dog model. Blood Adv 2:505-508
Herzog, Roland W; Nichols, Timothy C; Su, Jin et al. (2017) Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce. Mol Ther 25:512-522
Markusic, David M; Nichols, Timothy C; Merricks, Elizabeth P et al. (2017) Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models. J Transl Med 15:94
Nichols, T C; Hough, C; Agersø, H et al. (2016) Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies. J Thromb Haemost 14:894-905
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
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
Geist, Rebecca E; DuBois, Chase H; Nichols, Timothy C et al. (2016) Experimental Validation of ARFI Surveillance of Subcutaneous Hemorrhage (ASSH) Using Calibrated Infusions in a Tissue-Mimicking Model and Dogs. Ultrason Imaging 38:346-58
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
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
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

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