MODIFICATION OF PORCINE ISLETS FOR TRANSPLANTATION

用于移植的猪胰岛的改造

• 批准号: 6564349
• 负责人: Gordon Campbell Weir
• 金额: $ 21.13万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564349
• 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能力 产生胰岛素的细胞，这样它们就可以移植到患有 糖尿病。重点放在猪岛上，这将是遗传上的 经过改良以抵抗异种移植排斥反应。目标是： 1.利用猪新生胰腺细胞团(NPCCs)进行学习 更多关于前体细胞和原分化的胰腺细胞如何 发育成成熟的内分泌细胞。 2.利用不同的生长和分化来操纵复制和分化 分化因素，既优化了组织来源，又为 移植和加强基因转移的策略。 3.检测猪新生细胞移植到 了解裸鼠的生长能力、分化和 体内功能 4.腺病毒载体介导基因的特性研究 移植胰岛的转移和表达，并建立和 描述一种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 有成年和新生猪胰岛。 5.确定大鼠胰岛基因工程表达的程度 CTLA4Ig或FasL均可增强异种移植肾存活 小鼠糖尿病模型的建立及转基因需求的表征 表达和参与移植物存活的免疫机制。 6.为新生儿的有效转导创造条件 猪胰岛细胞，以便在异种模型中进行研究。