MODIFICATION OF PORCINE ISLETS FOR TRANSPLANTATION

用于移植的猪胰岛的改造

• 批准号: 6105815
• 负责人: Gordon Campbell Weir
• 金额: $ 12.01万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105815
• 关键词: Adenoviridae; animal genetic material tag; athymic mouse; cell transplantation; gene therapy; genetically modified animals; insulin; insulin dependent diabetes mellitus; laboratory rat; nonhuman therapy evaluation; pancreatic islet transplantation; pancreatic islets; swine; transfection /expression vector; transplantation immunology; xenotransplantation

The goal of this project is to improve the performance and survival of insulin producing cells so they can be transplanted into people with diabetes. The focus is upon porcine islets which will be genetically modified to resist xenograft rejection. The aims are: 1. To use porcine neonatal pancreatic cell clusters (NPCCs) to learn more about how precursor and protodifferentiated pancreatic cells develop into mature endocrine cells. 2. To manipulate replication and differentiation with various growth and differentiation factors to both optimize the tissue source for the transplantation and enhance gene transfer maneuvers. 3. To examine populations of porcine neonatal cells transplanted into nude mice to understand their growth capacity, differentiation and function in vivo 4. To study the characteristics of adenovirus vector-mediated gene transfer and expression in transplanted islets and to establish and characterize a lentivirus-based gene transfer system for islets. Experiments performed with rat islets represent a prelude to experiments with adult and neonatal porcine islets. 5. To determine the extent to which rat islets engineered to express either CTLA4Ig or FasL show enhanced graft survival in a xenogeneic mouse diabetes model and to characterize the requirements for transgene expression and the immune mechanisms involved in graft survival. 6. To establish conditions for the efficient transduction of neonatal porcine islet cells so they can be studied in xenogeneic models.

该项目的目标是提高性能和生存 产生胰岛素的细胞，以便将它们移植到患有糖尿病的人身上 糖尿病。 重点是猪胰岛，它将进行基因改造 进行修饰以抵抗异种移植排斥。 目标是： 1. 使用猪新生儿胰腺细胞簇（NPCC）来学习 更多关于前体细胞和原始分化胰腺细胞的信息 发育成成熟的内分泌细胞。 2. 通过各种生长和调控来操纵复制和分化 分化因子，以优化组织来源 移植并增强基因转移操作。 3. 检查移植到的猪新生细胞群 裸鼠了解其生长能力、分化和 体内功能 4. 研究腺病毒载体介导的基因特性 在移植胰岛中的转移和表达以及建立和 描述基于慢病毒的胰岛基因转移系统。 用大鼠胰岛进行的实验是实验的前奏 与成年和新生猪胰岛。 5. 确定大鼠胰岛工程表达的程度 CTLA4Ig 或 FasL 在异种移植物中表现出增强的移植物存活率 小鼠糖尿病模型并表征转基因的要求 表达和参与移植物存活的免疫机制。 6. 为新生儿高效转导创造条件 猪胰岛细胞，以便可以在异种模型中进行研究。