Innate Cellular Lectin-Mediated Binding of Xenogeneic Antigens

先天细胞凝集素介导的异种抗原结合

• 批准号: 7484257
• 负责人: MICHAEL A REES
• 金额: $ 25.39万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-09 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484257
• 关键词: Acids; Acute Liver Failure; Animal Organ; Animals; Annexin A1; Annexin A4; Annexins; Antigens; Binding; Blood; Carbohydrates; Cell Line; Cell Surface Receptors; Cell surface; Cells; Chinese Hamster; Climacteric; Cloning; Condition; Data; Development; Erythrocytes; Family suidae; Genetic Engineering; Glycopeptides; Glycophorin A; Hepatic; Heterophile Antigens; Human; Immune; Investigation; Kupffer Cells; Lectin; Lectin Receptors; Ligands; Liver; Mediating; Membrane Proteins; Mind; Modeling; Molecular; Monosaccharides; N-Acetylneuraminic Acid; Oligosaccharides; Organ; Organ Transplantation; Ovarian; Patients; Perfusion; Personal Satisfaction; Phenotype; Play; Pre-Clinical Model; Primates; Process; Proteins; Research Personnel; Role; Sialic Acids; Source; Sus scrofa; Technology; Testing; Thinking; Time; Transplantation; Work; Xenograft procedure; clinically relevant; design; improved functioning; insight; liver function; macrophage; prevent; receptor; success; sugar; tool

DESCRIPTION (provided by applicant): Organ transplantation has changed the lives of hundreds of thousands of patients. In fact, it is the success of transplantation that has led to its major limitation-there simply are not enough organs to meet the demand. Thus, researchers are looking for alternative sources of organs for transplantation. A strategy thought likely to succeed is the use of animal organs to replace failed human organs, a process known as xenotransplantation. Recent developments in genetic engineering and cloning technology have raised hopes that xenotransplantation will become a successful treatment within the next few decades. The pig is the animal felt to be the most appropriate source of organs in this regard. Extracorporeal liver perfusion (ECLP) has been suggested as one of the first applications of a vascularized porcine organ for the treatment of a patient. ECLP is felt to be a reasonable first choice because patients in fulminant liver failure have a lifethreatening condition and do not have alternative temporary means of support. In addition, ECLP could be used before long-term survival of vascularized organs has been achieved in a primate model as ECLP has been shown to provide hepatic support over a short period of time that is well within the current expected survival of vascularized porcine organs in primates. One of the barriers preventing the application of ECLP is the loss of erythrocytes that occurs when human blood perfuses a porcine liver. Further investigation has demonstrated that porcine Kupffer cells are responsible for the destruction of the human erythrocytes by a mechanism involving Kupffer cell surface protein receptor recognition of foreign human sugar molecules. Such sugar recognizing proteins are called lectins. Sialic acid has been identified as a component of the carbohydrate ligand being recognized and porcine annexins I, II and IV have been identified as potential lectin receptors responsible for the binding. Specific aims 1 and 2 propose to identify the exact sugars being recognized and to evaluate the role of porcine annexins as the receptor responsible for binding human erythrocytes. Specific aim 3 proposes to use this new information to design a substance that will prevent the loss of human erythrocytes during liver xenoperfusion and to test this substance in a pre-clinical model of extracorporeal porcine liver perfusion. This work will advance our understanding of macrophage recognition of foreign sugars from other species and make ECLP a more useful tool in treating fulminant hepatic failure.

描述（由申请人提供）： 器官移植改变了成千上万患者的生活。事实上，正是移植的成功导致了它的主要局限性--根本没有足够的器官来满足需求。因此，研究人员正在寻找用于移植的替代器官来源。一种被认为可能成功的策略是使用动物器官来替代失败的人体器官，这一过程被称为异种移植。基因工程和克隆技术的最新发展使人们对异种移植在今后几十年内成为一种成功的治疗方法产生了希望。在这方面，猪被认为是最合适的器官来源。体外肝灌注（ECLP）已被建议作为血管化猪器官治疗患者的首批应用之一。ECLP被认为是合理的首选，因为暴发性肝衰竭患者的病情危及生命，并且没有替代的临时支持手段。此外，在灵长类动物模型中实现血管化器官的长期存活之前，可以使用ECLP，因为已证明ECLP在短时间内提供肝脏支持，这完全在灵长类动物中血管化猪器官的当前预期存活范围内。阻止ECLP应用的障碍之一是当人血灌注猪肝时发生的红细胞损失。进一步的研究表明，猪枯否细胞通过涉及枯否细胞表面蛋白受体识别外源人糖分子的机制负责人红细胞的破坏。这种糖识别蛋白质被称为凝集素。唾液酸已被鉴定为被识别的碳水化合物配体的组分，猪膜联蛋白I、II和IV已被鉴定为负责结合的潜在凝集素受体。具体目标1和2提出确定被识别的确切糖，并评估猪膜联蛋白作为负责结合人红细胞的受体的作用。具体目标3建议使用该新信息设计一种可防止肝脏异种灌注期间人红细胞损失的物质，并在体外猪肝灌注的临床前模型中测试该物质。这项工作将促进我们对巨噬细胞识别来自其他物种的外源糖的理解，并使ECLP成为治疗暴发性肝功能衰竭的更有用的工具。