Thromboregulatory strategies to prolong xenograft survival.

延长异种移植物存活的血栓调节策略。

基本信息

批准号：
7898491
负责人：
SIMON C. ROBSON
金额：
$ 98.29万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898491
关键词：
Abbreviations Acute Address Allografting Alteplase Antibodies Anticoagulants Antigens Antithrombins Binding Proteins Biological Biological Models Blood Blood Circulation Blood Clot Blood Coagulation Factor Blood Platelets Blood Vessels Blood coagulation Bone Marrow Bone Marrow Cells Bone Marrow Transplantation CD31 Antigens Cells Cellular Immunity Charge Chimerism Chronic Kidney Failure Coagulation Process Complement Consumption Cyclophosphamide Cyclosporine Cyclosporins Data Deposition Development Diabetes Mellitus Disease Elements Endothelial Cells Engineering Enzymes Epitopes Esophageal Varix Event Excision Failure Family Family suidae Fibrin Fibrinolysis Fibroblasts Generations Genetic Engineering Goals Hemorrhage Heparitin Sulfate Human Immune Immunosuppressive Agents Individual Infarction Inflammation Inflammation Mediators Inflammatory Infusion procedures Injury Insulin Intervention Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Kinetics Link Liver Living Donors Maintenance Mediating Mediator of activation protein Miniature Swine Minor Modification Molecular Monkeys Mus Nature Nitric Oxide Nucleotides Operative Surgical Procedures Organ Organ Transplantation Papio Pathway interactions Pattern Phenotype Plasma Cells Platelet Activation Platelet Glycoproteins Portal Hypertension Portal vein structure Primates Procedures Process Prostaglandins I Protein C Proteins Protocols documentation Reaction Reagent Regulation Research Research Personnel Resistance Role Source System TFPI Testing Therapeutic Thrombin Thrombocytopenia Thrombomodulin Thromboplastin Thrombosis Thrombotic Thrombocytopenic Purpura Thymic Tissue Time Tissues Toxic effect Transaminases Transgenic Organisms Transplantation Treatment Protocols Umbilical vein Up-Regulation Vascular Endothelium Xeno Xenograft procedure antithrombin III-protease complex cell preparation clinical application clinical practice clinically relevant cytokine ectoADPase extracellular fluidity genetic manipulation heart xenograft implantation in vitro Model in vivo interest intravenous drip islet kidney xenograft meetings monocyte mutant neutrophil novel nuclear transfer nucleoside triphosphate overexpression portal vein thrombosis programs research study response vascular inflammation von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Xenotransplantation may be clinically feasible once the molecular barriers between species and mechanisms of graft loss or rejection are better understood. Xenograft survival would have to be also achieved without compromising the recipient to the extent that systemic toxicity would be encountered. In this regard, genetic engineering of swine, with xenograft modification to provide greater compatibility, has been of recent interest. Thrombotic and inflammatory reactions to porcine bone marrow (BM)-derived cells, infused pancreatic islets and the vasculature of organ grafts are linked to the difficulties in establishing mixed discordant chimerism, pancreatic islet-associated procoagulant injury and the development of xenograft microangiopathy. These responses are likely associated with humoral immune reactions to xenogeneic tissues. However, thrombotic processes with progressive xenograft vascular injury and infarction may be further exacerbated by documented intrinsic molecular incompatibilities in regulation of blood clotting between discordant species. An example of this would be the failure of natural porcine anticoagulants, such as thrombomodulin, to interact with human/primate coagulation factors, such as thrombin and Protein C. The development of the GalT-KO pig and consequent removal of the dominant xeno-antigen have been a major advance in xenotransplantation research. However, problems still persist in inducing tolerance by generating mixed xenogeneic chimerism, either by vascularized thymic tissues or the BM-derived cell approach in baboons. GalT-KO islets have not yet been tested but the current GalT-KO renal and cardiac xenograft limited survival times and associated vascular injury patterns still preclude clinical application. The goals of this application are to effectively manage graft thrombotic and vascular sequelae associated with GalT-KO pig-to-baboon renal grafting and those complications seen in islet xenotransplantation. We will evaluate transgenic approaches to over-express CD39, a key thromboregulatory protein and/or thrombomodulin in pigs. Transgenic porcine vascularized renal grafts and pancreatic islets over-expressing these human factors will be transplanted into baboons. Our strategies will include optimal immunosuppressive interventions with protocols to attempt induction of tolerance. These studies will be judged successful if novel, clinically relevant antithrombotic therapies can be then developed and applied.

描述（由申请人提供）：一旦可以更好地理解物种和移植物丢失或排斥的机制之间的分子屏障，可以在临床上可行。异种移植物的生存也必须达到不损害接受者的情况下，在遇到全身毒性的情况下。在这方面，猪的基因工程具有更大的兼容性，具有异种移植的修饰以提供更大的兼容性。对猪骨髓（BM）衍生的细胞，注入胰岛和器官移植物的脉管系统的血栓形成和炎症反应与建立混合不一致的嵌合，胰岛胰岛胰岛相关的Procogagulant损伤和发育的脑静脉损伤和发育的困难有关。这些反应可能与对异种组织的体液免疫反应有关。然而，在调节不一致物种之间血液凝结的固有分子不兼容时，可能会进一步加剧具有进行性异种移植血管损伤和梗塞的血栓形成过程。一个例子是，天然猪抗凝剂（例如血栓统治）与人/灵长类动物凝血因子（例如凝血酶和蛋白质C）相互作用。Galt-ko猪的发展以及随之而来的去除Xeno-antigen的去除已在Xenotrantplantaltation Research中取得了重大进展。然而，问题仍然存在于通过血管化胸腺组织或狒狒中BM衍生的细胞方法产生混合异类嵌合嵌合物来诱导耐受性。 Galt-KO胰岛尚未进行测试，但是当前的Galt-KO肾脏和心脏异种移植有限的生存时间和相关的血管损伤模式仍排除临床应用。该应用的目标是有效地管理与Galt-ko-ko-ko-to-baboon肾移植以及在胰岛异种移植中看到的并发症相关的移植血栓和血管后遗症。我们将评估过表达CD39的转基因方法，CD39是猪中的关键血小板调节蛋白和/或血小板调节蛋白。转基因猪血管化肾移植物和过表达这些人为因素的胰岛将被移植到狒狒中。我们的策略将包括最佳的免疫抑制干预措施，并通过方案尝试诱导耐受性。如果可以开发和应用新颖的，临床相关的抗血栓疗法，则这些研究将被认为是成功的。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hemostasis, bleeding and thrombosis in liver disease.

DOI：
10.15761/jts.1000182
发表时间：
2017-05
期刊：
Journal of translational science
影响因子：
0
作者：
Flores B;Trivedi HD;Robson SC;Bonder A
通讯作者：
Bonder A

Localization of plasma membrane bound NTPDases in the murine reproductive tract.

DOI：
10.1007/s00418-008-0551-3
发表时间：
2009-05
期刊：
Histochemistry and cell biology
影响因子：
2.3
作者：
Martín-Satué M;Lavoie EG;Pelletier J;Fausther M;Csizmadia E;Guckelberger O;Robson SC;Sévigny J
通讯作者：
Sévigny J

CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages.

CD39 和 CD73 活性在抗磷脂抗体诱导的流产小鼠模型中具有保护作用。

DOI：
10.1016/j.jaut.2017.10.009
发表时间：
2018
期刊：
Journal of autoimmunity
影响因子：
12.8
作者：
Samudra,AnushkaN;Dwyer,KarenM;Selan,Carly;Freddi,Susanna;Murray-Segal,Lisa;Nikpour,Mandana;Hickey,MichaelJ;Peter,Karlheinz;Robson,SimonC;Sashindranath,Maithili;Cowan,PeterJ;Nandurkar,HarshalH
通讯作者：
Nandurkar,HarshalH

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.

DOI：
10.1111/imr.12528
发表时间：
2017-03
期刊：
Immunological reviews
影响因子：
8.7
作者：
Allard B;Longhi MS;Robson SC;Stagg J
通讯作者：
Stagg J

Preservation of cochlear function in Cd39 deficient mice.

Cd39 缺陷小鼠耳蜗功能的保护。

DOI：
10.1016/j.heares.2009.03.009
发表时间：
2009
期刊：
Hearing research
影响因子：
2.8
作者：
Vlajkovic,SrdjanM;Housley,GaryD;Thorne,PeterR;Gupta,Rita;Enjyoji,Keiichi;Cowan,PeterJ;CharlesLiberman,M;Robson,SimonC
通讯作者：
Robson,SimonC