Coagulation Control To Protect Gaitko Lung and Liver Xenografts

凝血控制保护 Gaitko 肺和肝异种移植物

• 批准号: 8009659
• 负责人: Richard N Pierson
• 金额: $ 72.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009659
• 关键词: Address; Adhesions; Adsorption; Antibodies; Anticoagulants; Attenuated; Avidity; Binding; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; CD46 Antigen; Clinical; Clinical Trials; Coagulation Process; Complement; Complement Activation; Complement component C1s; DDAVP; Data; Disease; Endothelium; Engineering; Evaluation; Excision; Failure; Family suidae; Fibrin; Filtration; Glycoproteins; Goals; Heart; Hemorrhage; Hepatic; Hour; Human; Immunity; Immunosuppression; In Vitro; Inflammatory; Injury; Intervention; Kidney; Knowledge; Lepirudin; Life; Link; Liver; Lung; Mediating; Membrane Glycoproteins; Modeling; Molecular; Molecular Target; Neuraminidase; Organ; Organ Transplantation; Papio; Pathogenesis; Pathway interactions; Performance; Perfusion; Physiological; Plasma; Primates; Protein C; Proteins; Publishing; Reagent; Regimen; Relative (related person); Resources; Respiratory physiology; Role; Sepsis; Sialic Acids; Structure; Testing; Thrombin; Thrombocytopenia; Thrombomodulin; Thrombosis; Transplantation; VWF gene; Work; Xenograft procedure; activated Protein C; allotransplant; base; bivalirudin; clinical application; clinically relevant; complement pathway; ex vivo perfusion; experience; genetic regulatory protein; improved; inhibitor/antagonist; insight; kidney xenograft; liver transplantation; liver xenograft; lung injury; lung xenograft; neutrophil; novel; prevent; programs; receptor; success; sugar; thrombolysis; von Willebrand Factor; zanamivir

Hyperacute rejection ofthe heart and kidney is reliably prevented when GalTKO organs are used that additionally express a human complement pathway regulatory protein (hCPRP). In contrast, although GalTKO.hCPRP pig lung xenograft function is significantly prolonged relative to GalTKO or hCPRP lungs, lung injury nonetheless occurs within hours of transplantation into baboons or following perfusion with human blood. Similarly, platelet sequestration occurs almost immediately when GalTKO.hCPRP pig livers are orthotopically transplanted in baboons, and limits recipient survival. A number of molecular incompatibilities between pig endothelial membrane glycoproteins and primate platelet receptors and plasma coagulation pathway proteins probably explain the mechanistic basis of coagulation pathway dysregulation and platelet sequestration in lung and liver xenograft injury. These incompatibilities may also contribute to related problems in heart and kidney xenotransplants, thrombotic microangiopathy (TM) and consumptive coagulopathy (CC). In this Project we will take advantage ofthe GalTKO.hCPRP pig lung's particular avidity for platelet and neutrophil sequestration, and its propensity to amplify coagulation pathway activation. Using a combination of clinically available approaches to impact thromboregulation (DDAVP, to deplete donor vWF pretransplant; zanamivir, a sialydase inhibitor, to maintain sialic acid expression on circulating platelet receptors and associated vWF) and unique molecular targeting reagents (an anti-GPlB Fab and an antisialydase antibody), Aim 1 will test the hypothesis that GPlB/vWF, modulated by desialydation, mediate primate platelet and neutrophil sequestration by porcine endothelium. In Aim 2, GalTKO.hCPRP pig lungs that also express human thrombin pathway regulatory proteins (thrombomodulin or endothelial protein C receptor) will reveal whether molecular incompatibilities in this pathway contribute significantly to lung injury, and whether expression of these molecules is protective. Aim 3 will determine whether strategies arising from Aims 1 and 2 will consistently yield life-supporting function of a pig lung in a baboon, and whether a similar approach reliably prevents thrombocytopenia in a baboon supported by a GalTKO.hCPRP pig liver.

当使用Galtko器官时，可以可靠地防止对心脏和肾脏的过度抑制 另外表达人类补体途径调节蛋白（HCPRP）。相反，虽然 galtko.hcprp猪肺异种移植功能相对于Galtko或HCPRP肺显着延长， 然而 人血。同样，血小板隔离几乎在galtko.hcprp猪肝脏时立即发生 在狒狒中原位移植，并限制受体存活。 猪内皮膜糖蛋白和 灵长类动物血小板受体和血浆凝血途径蛋白可能解释了机械基础 肺和肝脏异种移植损伤中的凝结途径失调和血小板隔离。这些 不兼容也可能导致心脏和肾脏异种移植物，血栓形成的相关问题 微血管病（TM）和消耗性凝血病（CC）。 在这个项目中，我们将利用galtko.hcprp猪肺对血小板的特殊亲戚 和中性粒细胞固相，及其扩增凝血途径激活的倾向。使用 临床上可用方法的影响（DDAVP，耗尽供体VWF） 移植前； Zanamivir是一种辅助酶抑制剂，可在循环血小板上维持唾液酸表达 受体和相关的VWF）和独特的分子靶向试剂（抗GPLB FAB和抗疾病酶 抗体），AIM 1将检验以下假设：GPLB/VWF，通过deLydation调节，介导 猪内皮细胞的灵长类动物血小板和中性粒细胞隔离。在AIM 2中，Galtko.hcprp猪肺 还表达人类凝血酶途径调节蛋白（血小板结合蛋白或内皮蛋白C 受体）将揭示该途径中的分子不兼容性是否有显着贡献 损伤以及这些分子的表达是否具有保护性。 AIM 3将确定策略是否 源于目标1和2产生的将始终在狒狒中产生猪肺的生命支持功能，并且 类似方法是否可靠地阻止了由galtko.hcprp支持的狒狒中的血小板减少症 猪肝。