Small Animal Core

核心C的作用是为所有研究项目提供鼠标模型。我们将追求两个具体目标。 目标1包括：1)协调、购买和安置免疫缺陷(NOD/SCID和NOD/SCID/YC KO)小鼠，用于为所有项目(研究策略部分解释的项目3除外)制备人源化小鼠(见目标2)；以及2)维护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。这些小鼠将被用来评估CD47基因在猪造血祖细胞中的转导(项目2)，并准备用于评估人NK细胞对猪混合造血祖细胞移植耐受性的HU-小鼠 (项目3)。目的2提供人源化小鼠(HU小鼠)模型，包括：1)具有正常人体免疫系统的标准HU小鼠；2)猪胸腺移植的HU小鼠；3)表达人CD39转基因基因的HU小鼠；4)表达HLAE/人B2M/多肽三聚体的猪造血细胞嵌合HU小鼠。我们的方法是移植胎儿胸腺组织(肾被膜下)和CD34造血干/祖细胞(静脉注射)，以产生具有功能免疫系统的Hu-小鼠。在免疫缺陷小鼠身上。标准的HU小鼠将被用来测试用于非人类灵长类动物的免疫调节试剂/方案(项目1和2)。HLAE/人p2m/多肽三聚体表达的猪嵌合HU-小鼠将在项目3中评估猪细胞上NK细胞抑制配体表达诱导人NK细胞耐受的可能性。 对于猪胸腺移植物和人CD39过表达的HU小鼠，将在项目4中使用，以研究CD39在异种猪胸腺移植物中人类调节T细胞发育中的作用。 核心将准备和验证鼠标模型，然后执行拟议的实验(针对项目1和2)或向研究人员提供“随时可用的”模型(针对项目3和4)。正如每个研究组件中详细说明的那样，这些鼠标模型对于该计划项目的成功至关重要。

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.