GENE MODIFIED CLONED PIGS

基因修饰克隆猪

• 批准号: 7349805
• 负责人: THOMAS E STARZL
• 金额: $ 0.58万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349805
• 关键词: GENE; MODIFIED; CLONED; PIGS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ultimate objective of this proposal is to relieve the organ shortage crisis by genetic alteration of pigs so porcine tissues and organs can be transplanted to humans (i.e. xenotransplantation) with results equivalent to those attainable with allografts under conventional immunosuppression. Progress toward this objective has been precluded by the innate immune reaction of higher primate recipients that targets the alphaGal epitopes that are expressed on the surface of pig but not human cells. Having characterized the full genomic organization and transcriptional regulation of the alphaGT gene in several lower mammals (including pigs) and in all of the higher mammals (including humans), we are collaborating with PPL Therapeutics in their efforts to generate for the first time recombinant pig cells that have double alpha1,3GT allele knockout (KO). These double KO cells can be used for somatic cell nuclear transfer (cloning) to produce cloned double KO fetuses and piglets. We intend to fully characterize the molecular alterations and phenotypic qualities of the recombinant fetal cells, as well as the cells, tissues, or organs of the anticipated full-term cloned piglets. In addition, the double KO fetal cells, and the cells, tissues, and organs of these piglets will be tested in transgenic mouse models that will allow prediction of the innate and adaptive immune responses generated by alphaGal-negative higher primate recipients (including humans) to the genetically altered porcine xenografts.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项建议的最终目的是通过改变猪的基因来缓解器官短缺危机，以便将猪的组织和器官移植到人类身上(即异种移植)，结果与传统免疫抑制下的同种移植相当。高级灵长类动物受体的先天免疫反应针对的是猪细胞表面表达的α-Gal表位，而不是人类细胞表面的表位，这阻碍了实现这一目标的进展。在几种低等哺乳动物(包括猪)和所有高等哺乳动物(包括人)中表征了alphaGT基因的完整基因组组织和转录调控后，我们正在与PPL Treeutics合作，努力创造出首次具有双重alpha1，3GT等位基因敲除(KO)的重组猪细胞。这些双KO细胞可用于体细胞核移植(克隆)，以产生克隆的双KO胎儿和仔猪。我们打算充分描述重组胎儿细胞的分子变化和表型特征，以及预期的足月克隆仔猪的细胞、组织或器官。此外，双KO胎儿细胞以及这些小猪的细胞、组织和器官将在转基因小鼠模型中进行测试，这将允许预测AlphaGal阴性的高等灵长类受体(包括人类)对转基因猪移植产生的先天和获得性免疫反应。