Coagulation Control To Protect Gaitko Lung and Liver Xenografts

凝血控制保护 Gaitko 肺和肝异种移植物

基本信息

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
项目类别：
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

项目摘要

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，可以可靠地防止心脏和肾脏的超急性排斥反应另外还表达人类补体途径调节蛋白（hCPRP）。相比之下，虽然 GalTKO.hCPRP猪肺异种移植物功能相对于GalTKO或hCPRP肺显着延长，然而，肺损伤仍然发生在移植到狒狒体内或灌注后数小时内。人类的血液。同样，当 GalTKO.hCPRP 猪肝发生时，血小板几乎立即被隔离被原位移植到狒狒体内，限制了受体的生存。猪内皮膜糖蛋白和猪内皮膜糖蛋白之间的许多分子不相容性灵长类血小板受体和血浆凝固途径蛋白可能解释了肺和肝异种移植损伤中的凝血途径失调和血小板隔离。这些不相容性还可能导致心脏和肾脏异种移植、血栓形成等相关问题微血管病（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和力和中性粒细胞隔离，及其放大凝血途径激活的倾向。使用结合临床上可用的影响血栓调节的方法（DDAVP，以消耗供体 vWF）移植前；扎那米韦，一种唾液酸酶抑制剂，维持循环血小板上唾液酸的表达受体和相关的 vWF）和独特的分子靶向试剂（抗 GPlB Fab 和抗唾液酸酶抗体），目标 1 将检验以下假设：通过去唾液酸调节的 GPlB/vWF 介导猪内皮细胞对灵长类动物血小板和中性粒细胞的隔离。在目标 2 中，GalTKO.hCPRP 猪肺还表达人类凝血酶途径调节蛋白（血栓调节蛋白或内皮蛋白 C 受体）将揭示该途径中的分子不相容性是否对肺有显着影响损伤，以及这些分子的表达是否具有保护作用。目标 3 将决定策略是否由目标 1 和 2 产生的将持续在狒狒身上产生猪肺的生命支持功能，并且类似的方法是否能可靠地预防由 GalTKO.hCPRP 支持的狒狒的血小板减少症猪肝。