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GENE MODIFIED CLONED PIGS

基因修饰克隆猪

基本信息

批准号：
6884683
负责人：
Yifan Dai
金额：
$ 25.42万
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：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6884683
关键词：
clone cells diabetes mellitus disease /disorder model galactose gene expression genetic manipulation genetically modified animals immunocytochemistry laboratory mouse laboratory rabbit nonhuman therapy evaluation pancreatic islet transplantation surface antigens swine xenotransplantation

项目摘要

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.

这项提案的最终目的是通过基因治疗缓解器官短缺危机。对猪进行改造，使猪的组织和器官可以移植到人类身上（即，异种移植），其结果等同于常规免疫抑制。这一目标的进展一直受到阻碍，高等灵长类受体的先天免疫反应，其靶向在猪的细胞表面表达，而不是在人的细胞表面表达。在鉴定了完整的基因组后，几种低等哺乳动物α GT基因的组织和转录调控（包括猪）和所有高等哺乳动物（包括人类），我们正在合作，与PPL Therapeutics合作，首次生产重组猪细胞，具有双α 1，3GT等位基因敲除（KO）。这些双KO细胞可用于体细胞免疫。细胞核转移（克隆）以产生克隆的双KO胎儿和仔猪。我们打算充分表征重组胎儿的分子改变和表型质量细胞，以及预期的足月克隆仔猪的细胞、组织或器官。在此外，双KO胎儿细胞以及这些仔猪的细胞、组织和器官将被在转基因小鼠模型中进行了测试，这将允许预测先天和适应性 α Gal阴性高等灵长类动物受体（包括人类）产生的免疫应答转基因猪异种移植物。