Expression and function of the human PERV A receptors

人类 PERV A 受体的表达和功能

• 批准号: 6738145
• 负责人: Daniel R. Salomon
• 金额: $ 40.76万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738145
• 关键词: Retroviridae; antireceptor antibody; cell line; confocal scanning microscopy; disease /disorder proneness /risk; flow cytometry; fluorescence microscopy; genetically modified animals; human tissue; immunocytochemistry; immunofluorescence technique; immunoprecipitation; immunosuppression; in situ hybridization; laboratory mouse; lymphocyte; lymphocytic leukemia; monoclonal antibody; phenotype; protein structure function; receptor binding; receptor expression; transfection; virus cytopathogenic effect; virus infection mechanism; virus receptors; virus replication

DESCRIPTION (provided by applicant):The tremendous potential of solving the donor organ shortage with xenotransplantation of genetically engineered pigs is shadowed by the potential infection risks. Thus, if the xenotransplantation of pig tissues results in the activation of PERV viral replication, the risk of spreading this retrovirus to the human host is real, especially activated cells infiltrating a graft site under potent immunosuppression. That could result in an increased risk of leukemia or lymphoid tumors. In turn, if the transplant patient becomes infected there is also a potential of selecting and spreading a new variant of PERV adapted to the human host, first to immediate contacts and next to the public. Therefore, there is a critical need to advance our current understanding of the risk and biology of xenogeneic viral infection as part of a strategy for moving forward with clinical trials of xenotransplantation. The centerpiece for the present grant proposal is that we are the first group to clone the human receptors for PERV A. Therefore, the objectives of this proposal are to determine the expression of these receptors in human tissues as well as develop a transgenic mouse model expressing either or both the human PERV A receptors. If successful, this will be a major advance in the field allowing us to study the potential of PERV infection via the human receptor, compartmentalization, pathogenesis, viral adaptation impact of immunosuppression and risk of spread to uninfected animals. Specific Aim #I : Determine the expression of the human PERV A receptors in human tissue compartments and explore activation-induced changes in expression, cellular compartmentalization and possible functional impact of the PERV A receptors and PERV A virus in lymphocytes. Specific Aim #2: Produce transgenic mice for both human PERV A receptors (Al/A2) and determine the incidence, compartmentalization, phenotype and risk of PERV infection in this novel small animal model.

描述（由申请人提供）：通过潜在的感染风险掩盖了解决供体器官短缺的巨大潜力。因此，如果猪组织的异种移植会导致PerV病毒复制的激活，则将该逆转录病毒扩散到人宿主的风险是真实的，尤其是活化的细胞在有效的免疫抑制下渗透了移植物。这可能导致白血病或淋巴样肿瘤的风险增加。反过来，如果移植患者被感染了，也有可能选择和传播适合人类宿主的新变体的PERV，首先是立即接触并在公众旁边。因此，迫切需要促进我们目前对异类病毒感染的风险和生物学的理解，这是通过异种移植临床试验进行策略的一部分。当前授予建议的核心是我们是第一个克隆人类受体的群体。因此，该提案的目标是确定这些受体在人体组织中的表达，并开发出表达人Perv A受体的转基因小鼠模型。如果成功的话，这将是该领域的重大进步，使我们能够通过人体受体，分隔，发病机理，免疫抑制的病毒适应影响以及对未感染动物的传播风险来研究PerV感染的潜力。特定目标#I：确定人类组织室中人类PerV A受体的表达，并探索激活诱导的表达变化，细胞隔室化以及PERV A受体和PerV A在淋巴细胞中的可能影响。特定目标＃2：在这种新型的小动物模型中，为人类PerV A受体（Al/A2）产生转基因小鼠（Al/A2），并确定PerV感染的发生率，分隔，表型和风险。