Multi-Parametric Characterization of Human Islets: Predictor of Islet Quality, Po

人类胰岛的多参数表征：胰岛质量的预测因子 Po

• 批准号: 7168168
• 负责人: LUIS Alberto FERNANDEZ
• 金额: $ 86.73万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7168168
• 关键词: clinical research; culture; glucose; human; insulin; pancreas; solutions; transplantation

DESCRIPTION (provided by applicant): Islet transplantation has emerged as a promising option for restoring normal blood sugar control in people with Type 1 diabetes. However, key biological and institutional roadblocks hamper widespread utilization of this therapeutic strategy. Primary among these is the inability to recover a sufficient number of high quality islets, which is highly dependent pancreas preservation. Second, the absence of rapid, accurate, and sensitive pre-transplant test(s) that correlate with post-transplant function (i.e. potency assays) limits our ability to distinguish "healthy" preparations from those that will function poorly. Furthermore, high materials and equipment costs, the need for highly trained personnel and compulsory compliance with cGMP regulations makes islet isolation a difficult technology to consistently reproduce in every transplant program. For these reasons, methods should be developed that improve the ability to predict whether an islet preparation has the ability to function in the recipient after transplantation, and networks of regionalized islet isolation centers should be developed to minimize cold ischemic time and reduce institutional and financial hurdles. A successful Islet Transplant Program and isolation team has been established at the University of Wisconsin-Madison. The main goal of this application is to implement a series of quantitative measures of islet viability and functional potency in a regionalized pancreas recovery and islet distribution network and validate the ability of these parameters to predict islet graft function in patients. The proposal's specific aims are: 1) To distribute superior quality human islets for transplantation and research to members of a local islet research and transplant consortium and the ICR network based on a multi-parametric characterization of predictors of quality, potency and function. 2) To improve the quality of islet preparations by taking a three-pronged approach to sequentially optimize pancreas preservation, islet isolation, and post-isolation culture. Using the sensitive assessment tools, we will first test the effect of a novel trophic factor based preservation solution. We will also develop methods to minimize damage of islets during isolation, culture, and transportation focusing focusing on the reduction of ROS formation and the recovery of a "normal" metabolic state through supplementation of anti-oxidants to the isolation and culture media and optimization of culture pH, oxygen tension, and temperature. With this quality improvement program in place, we are confident we can provide over 20 million high quality islets over a five year period to ICR investigators and facilitate the development of additional islet transplantation programs to serve the diabetes community.

描述（由申请人提供）：胰岛移植已成为恢复1型糖尿病患者正常血糖控制的有前途的选择。但是，关键的生物学和机构障碍障碍者广泛利用了这种治疗策略。其中的主要是无法恢复足够数量的高质量胰岛，这是高度依赖的胰腺保存。其次，缺乏与移植后功能相关的快速，准确和敏感的移植前测试（即效力分析）限制了我们将“健康”制剂与功能较差的制剂区分开的能力。此外，高材料和设备成本，对训练有素的人员的需求以及对CGMP法规的强制性遵守，这使得胰岛隔离成为一个很难在每个移植计划中始终繁殖的技术。由于这些原因，应开发方法，以提高预测移植后胰岛准备是否具有在受体中发挥功能的能力，并应开发区域化胰岛隔离中心的网络以最大程度地减少冷缺血时间并减少机构和财务障碍。威斯康星大学麦迪逊分校已经建立了一个成功的胰岛移植计划和隔离团队。该应用的主要目的是在区域化胰腺恢复和胰岛分布网络中实施一系列胰岛活力和功能效力的定量测量，并验证这些参数预测患者胰岛移植功能的能力。该提案的具体目的是：1）基于质量，效力和功能预测指标的多参数表征，将卓越的人类胰岛分发给本地胰岛研究和移植联盟的成员以及ICR网络。 2）通过采用三管齐下的方法来依次优化胰腺保存，胰岛隔离和分离后培养物，以提高胰岛制剂的质量。使用敏感的评估工具，我们将首先测试基于营养因子的新型保存解决方案的效果。我们还将开发方法，以最大程度地降低胰岛的损害，重点关注ROS形成的减少以及通过补充抗氧化剂对隔离和培养基的补充以及优化培养物pH，氧气张力和温度的优化，以减少ROS形成和恢复“正常”代谢状态。有了这个质量改进计划，我们相信我们可以在五年内提供超过2000万个高质量的小岛，以ICR调查人员并促进开发其他胰岛移植计划，以服务于糖尿病社区。