Immunodeficient Pigs for Stem Cell­-Based Regenerative Medicine

用于干细胞再生医学的免疫缺陷猪

• 批准号: 9384776
• 负责人: Jorge A Piedrahita
• 金额: $ 46.04万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384776
• 关键词: Address; Animal Model; Animals; B-Lymphocytes; Biological Assay; Biological Models; Blood; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Stem Cell Transplantation; CD34 gene; CD47 gene; Cardiac; Cell Maturation; Cell Survival; Cells; Chondrocytes; Communicable Diseases; Complex; Data; Development; Dimensions; Engraftment; Environment; Epithelial Cells; Family suidae; Genes; Genetic Engineering; Genetic Recombination; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; Hematopoietic stem cells; Human; IL2RG gene; Immune; Immune response; Immune system; Immunodeficient Mouse; Immunology; Interleukin 2 Receptor Gamma; Interleukin-3; Islet Cell; KIT gene; Liver; Longevity; Lymphoid Cell; Macrophage Colony-Stimulating Factor; Manuscripts; Methods; Modeling; Modification; Mus; Muscle Cells; Mutation; Myelogenous; Myeloid Cells; Myeloproliferative disease; Natural Killer Cells; Neurons; Organ; Output; Peripheral; Phagocytosis; Physiology; Population; Preparation; Production; Regenerative Medicine; Reporting; Request for Applications; Research Infrastructure; Research Personnel; Rodent; SHPS-1 protein; Spleen; Stem cells; System; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Time; Transgenic Organisms; United States National Institutes of Health; Xenograft procedure; allograft rejection; base; bone cell; cytokine; experience; human stem cells; humanized mouse; improved; improved functioning; in vivo; lymph nodes; lymphoid neoplasm; macrophage; migration; mutant; new technology; peripheral blood; pig genome; preference; stem; stem cell niche; tumor growth

The goal of engrafting human cells into other species has been pursued for six decades. This goal remains and there are multiple labs across the world that are using, and improving humanized mice to address a range of high impact biomedical questions. However there is a need for developing systems in species that more closely resemble humans in size, physiology and longevity. The pig offers an exceptional and perhaps the best system for this purpose. Pigs are widely available and the life span, and cell and organ physiology more closely approximates those of human. Pigs are readily bred, born in litters and amenable to genetic engineering. Additionally, recent advances in gene editing have allowed the development of complex multi- transgenic pigs at very high efficiencies. We propose to introduce changes into the genome of pigs so as to enhance their ability to host human cells without rejection. We will focus on reducing phagocytosis of human cells by pig macrophages, enhancing the bone marrow stem cell niche so human cells can engraft at higher efficiencies, and providing a cytokine environment that favors human versus pig cells. Completion of these aims will result in the development of a new large animal model capable of robust and functional engraftment with human stem cells.

将人类细胞移植到其他物种中的目标已经追求了60年。这一目标仍然存在 世界各地有多个实验室正在使用和改进人性化鼠标，以解决一系列问题 高影响力的生物医学问题。然而，有必要在更多的物种中开发系统 在体型、生理和寿命上都与人类极为相似。猪提供了一种特殊的，也许是最好的 系统用于此目的。猪的使用范围广，寿命长，细胞和器官生理学更多 与人类的非常接近。猪很容易繁殖，生在窝子里，并易于遗传 工程学。此外，基因编辑方面的最新进展使复杂的多基因 转基因猪的效率非常高。我们建议在猪的基因组中引入改变，以便 增强它们在不发生排斥反应的情况下寄生人类细胞的能力。我们将重点减少人的吞噬功能 通过猪的巨噬细胞，增强骨髓干细胞的生态位，使人类细胞可以移植到更高的 效率，并提供有利于人类细胞而不是猪细胞的细胞因子环境。完成这些工作 AIMS将导致一种新的大型动物模型的开发，该模型能够健壮且具有功能植入 使用人类干细胞。