CANINE COAGULOPATHIES

犬凝血病

• 批准号: 7391962
• 负责人: URS GIGER
• 金额: $ 0.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391962
• 关键词: CANINE; COAGULOPATHIES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Manv hereditary coagulopathies have been reported in dogs and few of these disorders have been characterized and serve as disease homologues to study the pathogenesis and to develop novel therapies including recombinant therapy and gene transfer. Fibrinogen Deficiency: We have identified a mixed breed dog with excessive post-operative hemorrhage due to a severe hypofibrinogenemia. This dog has severally prolonged screening coagulation times and by functional as well as protein assays very low fibrinogen levels. A lack of fibrinogen prevents the formation of any fibrin clot and also is expected to affect wound healing. This is the only animal with a naturally occurring hypofibrinogenemia, although transgenic mice have been produced. As we have access to this dog studies are planned to further characterize the biochemical and molecular basis of this defect. Factor VII Deficiency We have identified several Beagles in the pet population with a mild to moderate bleeding tendency due to a hereditary factor VII deficiency. These animals have persistently 5% of control factor VII activity and no inhibitor has been found. Other affected Beagles have been found in research animal colonies of pharmaceutical companies, while performing drug studies based upon a prolonged partial thromboplastin time. Recombinant human factor VII has recently been shown to be effective in a variety of coagulopathies including hemophilia as it can bypass the defect. Therefore the molecular characterization and establishment of a dog colony with factor VII deficiency would be highly desirable. These studies in collaboration with Mary Beth Callan VMD and Kathy High MD PhD at the Children Hospital of Philadelphia, led to the discover of a single missense mutation and a severally dysfunctional protein. A simple reliable DNA test has been developed to screen for carriers and factor VII deficient Beagles, thereby permitting the establishment of a colony to study novel gene transfer approaches. Hemophilia A: After the initial description of an inversion mutation in a factor VIII deficient dog colony similar to what is the major molecular mechanism in hemophilic humans, we have been examining other hemophilic dogs¿ DNA for this inversion in collaboration with Jay Lozier PhD at NIH. Of the five initiallydogs none had this form of a molecular defect and further studies are in progress. Factor XI Deficiency: We had earlier described factor XI deficiency in Kerry Blue Terriers which experience a delayed post-operative hemorrhagic diathesis. Recently we identified two deficient dogs from a major breeder and with cooperation we are planning to investigate the molecular defect. This should be readily achievable as the entire genomic sequence is now available from the canine genome project. There are still questions regarding the precise mode of inheritance (recessive verus incomplete dominant) and no other therapeutic options other than fresh frozen plasma are currently available. Although there are cattle with factor XI deficiency, this is the only naturally occurring animal suitable for further labortary investigations of novel therapeutic strategies. Von Willebrand Disease Doberman pinschers have a high prevalence of type I von Willebrand disease. Type I refers to the proportional deficiency of all multimeric sizes of von Willebrand factor. We have utilized this animal model to further characterize the effect of desmopressin, a vasopressin analog, which is commonly used in the treatment of human von Willebrand disease but its mechanism is poorly understood. We learned that the effect of desmopressin is not dependent on platelet associated von Willebrand factor and either not solely or not at all related to the multimeric size of the von Willebrand factor. Further mechanisms related to the endothelium are being examined.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。许多遗传性凝血病已在犬中报道，这些疾病中很少有被表征并作为疾病同源物来研究发病机制和开发新的治疗方法，包括重组治疗和基因转移。 纤维蛋白原缺乏症：我们发现了一只混血犬，由于严重的低纤维蛋白原血症导致术后出血过多。该犬的筛选凝血时间分别延长，功能和蛋白质测定结果显示纤维蛋白原水平极低。缺乏纤维蛋白原可防止任何纤维蛋白凝块的形成，并且预计也会影响伤口愈合。这是唯一的动物与自然发生的低纤维蛋白原血症，虽然转基因小鼠已经产生。由于我们有机会获得这种狗的研究计划，以进一步表征这种缺陷的生化和分子基础。 因子VII缺乏症我们已经确定了几个比格犬的宠物人口有轻度至中度出血倾向，由于遗传因子VII缺乏症。这些动物有持续5%的控制因子VII的活动，没有抑制剂已被发现。其他受影响的比格犬已被发现在研究动物的制药公司的殖民地，而进行药物研究的基础上延长部分凝血活酶时间。重组人因子VII最近已被证明是有效的，在各种凝血病，包括血友病，因为它可以绕过缺陷。因此，具有因子VII缺陷的犬群体的分子表征和建立将是高度期望的。这些研究与费城儿童医院的玛丽贝丝卡兰医学博士和凯西高医学博士合作，发现了一个单一的错义突变和一个严重功能失调的蛋白质。已经开发了一种简单可靠的DNA测试来筛选载体和VII因子缺陷的比格犬，从而允许建立一个菌落来研究新的基因转移方法。 血友病A：在最初描述了一个因子VIII缺乏的狗群中的倒位突变后，类似于血友病人的主要分子机制，我们一直在与NIH的Jay Lozier博士合作研究其他血友病狗的DNA。在最初的五只狗中，没有一只有这种形式的分子缺陷，进一步的研究正在进行中。 因子XI缺乏症：我们先前描述了克里蓝梗犬的因子XI缺乏症，这些犬经历了延迟的术后出血素质。最近，我们从一个主要的育种者那里发现了两只缺陷犬，我们计划合作调查分子缺陷。这应该很容易实现，因为整个基因组序列现在可以从犬基因组计划中获得。关于确切的遗传模式（隐性与不完全显性）仍然存在问题，目前除了新鲜冷冻血浆外，没有其他治疗选择。虽然有牛因子XI缺乏症，这是唯一的自然发生的动物适合进一步实验室研究的新的治疗策略。 血管性血友病杜宾犬I型血管性血友病的患病率很高。I型是指血管性血友病因子的所有多聚体大小的比例缺陷。我们已经利用这种动物模型来进一步表征去氨加压素的作用，去氨加压素是一种加压素类似物，其通常用于治疗人血管性血友病，但其机制知之甚少。我们了解到去氨加压素的作用不依赖于血小板相关的血管性血友病因子，并且不完全或根本不与血管性血友病因子的多聚体大小相关。与内皮相关的进一步机制正在研究中。