Immunodeficient Pigs for Stem Cell-Based Regenerative Medicine

用于干细胞再生医学的免疫缺陷猪

基本信息

批准号：
9766880
负责人：
Jorge A Piedrahita
金额：
$ 44.71万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
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/9766880
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 Infrastructure 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 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

项目摘要

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的目标已经追求了六十年。这个目标依然存在世界各地有多个实验室正在使用和改进人源化小鼠来解决一系列问题高影响力的生物医学问题。然而，需要在物种中开发更多的系统在体型、生理结构和寿命方面与人类非常相似。猪提供了一种特殊的，也许是最好的为此目的的系统。猪的用途广泛，寿命长，细胞和器官生理学更多非常接近人类。猪很容易繁殖，一窝出生并且服从遗传工程。此外，基因编辑的最新进展使得复杂的多基因技术的发展成为可能。转基因猪的效率非常高。我们建议对猪的基因组进行改变，以便增强它们宿主人类细胞而不发生排斥的能力。我们将专注于减少人类的吞噬作用猪巨噬细胞，增强骨髓干细胞生态位，使人类细胞能够以更高的速度移植效率，并提供有利于人类细胞和猪细胞的细胞因子环境。完成这些目标将导致开发出一种能够稳健且功能性移植的新型大型动物模型与人类干细胞。