Small Animal Core

小动物核心

• 批准号: 8190136
• 负责人: YONG-GUANG YANG
• 金额: $ 36.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190136
• 关键词: Animals; CD34 gene; CD47 gene; Cells; Chimera organism; Chimerism; Clinical; Engraftment; Family suidae; Fibrous capsule of kidney; Genes; Goals; Hematopoietic; Housing; Human; Immune system; Immunodeficient Mouse; Instruction; Laboratories; Ligands; Modeling; Mus; Natural Killer Cells; Organ Donor; Peptides; Protocols documentation; Reagent; Regulatory T-Lymphocyte; Research; Research Personnel; Research Project Grants; Role; Solutions; Stem cell transplant; Stem cells; T-Cell Development; Testing; Thymic Tissue; Thymus Gland; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Transplantation; Xenograft procedure; cytokine; end-stage organ failure; fetal; mouse model; nonhuman primate; progenitor; programs; research study; stem; success

The role of Core C is to provide mouse models to all research projects. We will pursue two specific aims. Aim 1 includes: 1) coordinating, purchasing and housing immunodeficient (NOD/SCID and NOD/SCID/yc KO) mice, which will be used to prepare humanized mice (see Aim 2) for all projects (except Project 3, as explained in the Research Strategies section); and 2) maintaining and producing immunodeficient porcine cytokine transgenic mice. The porcine cytokine transgenic mice generated in this laboratory provide an excellent murine model for porcine hematopoietic stem/progenitor cell transplantation. These mice will be used to evaluate CD47 gene transduction in porcine hematopoietic progenitors (Project 2), and to prepare hu-mice for assessing human NK cell tolerance to porcine xenografts by mixed hematopoietic chimerism (Project 3). Aim 2 is to provide humanized mouse (hu-mouse) models, including: 1) 'standard' hu-mice with a functional human immune system; 2) hu-mice with porcine thymic grafts; 3) transgenic hu-mice that express human CD39 transgenes, and 4) porcine chimeric hu-mice with porcine hematopoietic cells expressing a HLA-E/human B2m/peptide trimer. Our approach to generating hu-mice with a functional immune system is to transplant fetal thymus tissue (under renal capsule) and CD34+ hematopoietic stem/progenitor cells (i.v.) in immunodeficient mice. The 'standard' hu-mice will be used to test the immunoregulatory reagents/protocols to be used in non-human primates (Projects 1 and 2). The HLAE/ human p2m/peptide trimer-expressing porcine chimeric hu-mice will be used to assess the potential of NK cell inhibitory ligand expression on porcine cells to induce human NK cell tolerance in Project 3. Hu-mice with porcine thymic grafts and human CD39-overexpresing hu-mice will be used in Project 4 to investigate the role of CD39 in human regulatory T cell development in xenogeneic porcine thymic grafts. The core will prepare and validate the mouse models, and then either perform the proposed experiments (for Projects 1 and 2) or provide 'ready-to-use' models to the investigators (for Projects 3 and 4). As detailed in each research components, these mouse models are essential to the success of this program project.

Core C的作用是为所有研究项目提供小鼠模型。我们将追求两个具体目标。 目标1包括：1）协调、购买和饲养免疫缺陷（NOD/SCID和NOD/SCID/yc KO）小鼠，这些小鼠将用于为所有项目（除项目3外，如研究策略部分所述）制备人源化小鼠（见目的2）; 2）维持和生产免疫缺陷猪细胞因子转基因小鼠。本实验室建立的猪细胞因子转基因小鼠为猪造血干/祖细胞移植提供了良好的小鼠模型。这些小鼠将用于评估猪造血祖细胞中的CD 47基因转导（项目2），并制备用于通过混合造血嵌合体评估人NK细胞对猪异种移植物耐受性的hu-mice （项目3）。目的2是提供人源化小鼠（hu-mouse）模型，包括：1）具有功能性人免疫系统的“标准”hu-mouse; 2）具有猪胸腺移植物的hu-mouse; 3）表达人CD 39转基因的转基因hu-mouse;和4）具有表达HLA-E/人B2 m/肽三聚体的猪造血细胞的猪嵌合hu-mouse。我们产生具有功能性免疫系统的hu小鼠的方法是移植胎儿胸腺组织（在肾包膜下）和CD 34+造血干/祖细胞（i. v.）在免疫缺陷小鼠中。“标准”hu-mice将用于检测非人灵长类动物中使用的免疫调节试剂/方案（项目1和2）。在项目3中，HLAE/人p2 m/肽三聚体表达猪嵌合人鼠将用于评估猪细胞上NK细胞抑制性配体表达诱导人NK细胞耐受性的潜力。胡鼠属 将在项目4中使用猪胸腺移植物和人CD 39过表达的hu小鼠，以研究CD 39在异种猪胸腺移植物中人调节性T细胞发育中的作用。 核心将准备和验证小鼠模型，然后执行拟议的实验（项目1和2）或向研究人员提供“即用型”模型（项目3和4）。正如每个研究部分所详述的那样，这些小鼠模型对于该项目的成功至关重要。