Maintenance Of Animal Models Of Human Hemophilia And VWD
Timothy Charles Nichols, Professor
Medicineuniversity Of North Carolina Chapel Hill
Grant 5R24HL063098-11 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: 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 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. (End of )
Project start date: 2008-09-15
Project end date: 2013-06-30
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Maintenance Of Animal Models Of Human Hemophillia &; VWD
Timothy Charles Nichols, Professor
Medicineuniversity Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 5R24HL063098-09 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: This purpose of this resource grant is to function as a core to maintain and create dogs with hemophilia A and B and von Willebrand disease (vWD) for collaborations with other investigators. In the first 3 years of funding, collaborations with at least 12 teams of investigators have been reported in 12 manuscripts. The research is funded on 18 separate research grants. Our objectives in this Resource Grant 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 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 modeling human hemophilia A, hemophilia B, and vWD were identified by Dr. Kenneth M. Brinkhous and have been maintained for >50 years in Chapel Hill largely through NIH support. 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. Research using the FOBRL dogs 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. Current research with these dogs addresses several unmet national needs including developing new treatments for bleeding, and determining the acute and chronic sequelae of gene therapy on genetic diseases. These dogs constitute an important national resource and are recommended by many investigators and advisory boards as essential for pre-clinical testing of new treatments for the hemophilias, vWD, and hemorrhage. The use of these hemophilic dogs has more than doubled during the past two decades. 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. The survival of the FOBRL colony would 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. This Resource Grant is essential to ensure the survival of the colony in an established, successful environment
Keywords: animal colony, biomedical facility, disease /disorder model, dog, hemophilia A, hemophilia B, von Willebrand`s disease animal breeding, animal care, blood bank, blood coagulation test, genetic disorder
Project start date: 1999-07-01
Project end date: 2008-06-30
5R24HL063098-09 (2007): $664967
Maintenance Of Animal Models Of Human Hemophillia & VWD
Timothy Charles Nichols, Professor
University Of North Carolina Chapel Hill Office Of Sponsored Research Chapel Hill, Nc 27599
Grant 5R24HL063098-08 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: This purpose of this resource grant is to function as a core to maintain and create dogs with hemophilia A and B and von Willebrand disease (vWD) for collaborations with other investigators. In the first 3 years of funding, collaborations with at least 12 teams of investigators have been reported in 12 manuscripts. The research is funded on 18 separate research grants. Our objectives in this Resource Grant 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 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 modeling human hemophilia A, hemophilia B, and vWD were identified by Dr. Kenneth M. Brinkhous and have been maintained for >50 years in Chapel Hill largely through NIH support. 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. Research using the FOBRL dogs 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. Current research with these dogs addresses several unmet national needs including developing new treatments for bleeding, and determining the acute and chronic sequelae of gene therapy on genetic diseases. These dogs constitute an important national resource and are recommended by many investigators and advisory boards as essential for pre-clinical testing of new treatments for the hemophilias, vWD, and hemorrhage. The use of these hemophilic dogs has more than doubled during the past two decades. 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. The survival of the FOBRL colony would 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. This Resource Grant is essential to ensure the survival of the colony in an established, successful environment.
Keywords: animal colony, biomedical facility, disease /disorder model, dog, hemophilia A, hemophilia B, von Willebrand s disease, animal breeding, animal care, blood bank, blood coagulation test, genetic disorder
Project start date: 1999-07-01
Project end date: 2008-06-30
5R24HL063098-08 (2006): $666604
5R24HL063098-07 (2005): $671832
5R24HL063098-06 (2004): $655869
MAINTENANCE OF ANIMAL MODELS OF HUMAN HEMOPHILIA AND VWD
Timothy Charles Nichols, Professor
Medicineuniversity Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 5R24HL063098-03 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: 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
Keywords: animal colony, blood coagulation disorder, disease /disorder model, hemophilia A, hemophilia B, von Willebrand`s disease dog
Project start date: 1999-07-01
Project end date: 2003-06-30
5R24HL063098-03 (2001): $564031
5R24HL063098-02 (2000): $548879
Grants awarded to Timothy Charles Nichols
Maintenance Of Animal Models Of Human Hemophillia And VWD
Timothy Charles Nichols, Professor
University Of North Carolina Chapel Hill Office Of Sponsored Research Chapel Hill, Nc 27599
Grant 2R24HL063098-05 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: This purpose of this resource grant is to function as a core to maintain and create dogs with hemophilia A and B and von Willebrand disease (vWD) for collaborations with other investigators. In the first 3 years of funding, collaborations with at least 12 teams of investigators have been reported in 12 manuscripts. The research is funded on 18 separate research grants. Our objectives in this Resource Grant 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 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 modeling human hemophilia A, hemophilia B, and vWD were identified by Dr. Kenneth M. Brinkhous and have been maintained for >50 years in Chapel Hill largely through NIH support. 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. Research using the FOBRL dogs 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. Current research with these dogs addresses several unmet national needs including developing new treatments for bleeding, and determining the acute and chronic sequelae of gene therapy on genetic diseases. These dogs constitute an important national resource and are recommended by many investigators and advisory boards as essential for pre-clinical testing of new treatments for the hemophilias, vWD, and hemorrhage. The use of these hemophilic dogs has more than doubled during the past two decades. 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. The survival of the FOBRL colony would 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. This Resource Grant is essential to ensure the survival of the colony in an established, successful environment.
Keywords: animal colony, biomedical facility, disease /disorder model, dog, hemophilia A, hemophilia B, von Willebrand s disease, animal breeding, animal care, blood bank, blood coagulation test, genetic disorder
Project start date: 1999-07-01
Project end date: 2008-06-30
2R24HL063098-05 (2003): $700129
Maintenance Of Animal Models Of Human Hemophilia And VWD
Timothy Charles Nichols, Professor
Medicineuniversity Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 2R24HL063098-10 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: 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 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. (End of )
Project start date: 2008-09-15
Project end date: 2013-06-30
2R24HL063098-10 (2008): $730361
Timothy Charles Nichols, Professor
Children s Hospital Of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318
Grant 5P01HL064190-089003 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: The Francis Owen Blood Research Laboratory (FOBRL) will be the location of the Animal Core in this Program Project Grant (PPG) for Gene Therapy of Hemophilia. Our main objective is to use dogs with hemophilia A and hemophilia B to determine the most efficient and least toxic method of gene therapy for these inherited disorders and to monitor the expression and persistence of F.VIII and F.IX. We hypothesize that replacement of F.VIII and F.IX by gene therapy will correct the bleeder phenotype in hemophilia A and B dogs, respectively. The FOBRL, established in 1960 and dedicated to the preservation and study of severely affected animal models of bleeding disorders, has been a resource for the study of canine hemophilia A and B. Both canine hemophilia A and B in the FOBRL colony are inherited as a sex-linked recessive traits; hemophilia A is due to an intron 22 inversion and hemophilia B is due to a point mutation in the catalytic domain of F.IX. Affected dogs have no detectable antihemophilic factor functionally or antigenically. Infusion of canine or human F.VIII and F.IX concentrates corrects prolonged partial thromboplastin times and halts the severe bleeding episodes characteristic of the hemophilias. Correction of canine hemophilia A and B by liver transplantation presaged successful vector-mediated gene therapy. This strain of hemophilia B dogs is the first animal model of hemophilia to enjoy long-term benefit of gene therapy with continuous expression of canine F.IX mediated by AAV-vectors from the High laboratory for over 7 years without production of anti-canine F.IX antibodies. Some dogs have exhibited a lower bleeding rate supporting our hypothesis. Current limitations of hemophilia gene therapy include low levels of transgene expression and the relative paucity of strategies for hemophilia patients with inhibitory antibodies. The Core function, then, is to provide professional and technical personnel and laboratory facilities for the conduct of F.VIII and F.IX gene transfer and vector toxicity studies for this PPG to address these limitations through novel strategies proposed in each of the four projects. Production of the hemophilic dogs dedicated to this PPG is supported by HL63098 "Maintenance of Animal Models of Hemophilia and VWD." This core will support experimental dogs, expert personnel for liver surgery, histochemical and morphological hepatic pathology, and determination of both therapeutic levels and toxic profiles of immunosuppressive agents, transportation of dogs for experimental procedures, and storage of plasmas, gross specimens, preserved tissues, and molecular materials (DNA, RNA, constructs, cell lines, etc.) from experimental and control dogs. These hemophilic dogs with the accompanying professional and technical support are a unique resource for basic studies focused on developing methods for gene therapy of hemophilia and testing novel gene expression and transfer vectors.
Keywords: animal colony, biomedical resource, dog, gene therapy, hemophilia A, hemophilia B, nonhuman therapy evaluation, coagulation factor IX, coagulation factor VIII, disease /disorder model, gene expression, sex linked trait, toxicology, transfection /expression vector, blood chemistry, histochemistry /cytochemistry, pathology
MAINTENANCE OF ANIMAL MODELS OF HUMAN HEMOPHILIA AND VWD
Timothy Charles Nichols, Professor
Medicineuniversity Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 1R24HL063098-01 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: 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
Keywords: Christmas disease, animal colony, blood coagulation disorder, disease model, hemophilia A, von Willebrand`s disease dog
Project start date: 1999-07-01
Project end date: 2003-06-30
1R24HL063098-01 (1999): $553854