Multi-Parametric Characterization of Human Islets

人类胰岛的多参数表征

• 批准号: 7291086
• 负责人: LUIS Alberto FERNANDEZ
• 金额: $ 87.78万
• 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/7291086
• 关键词: Multi; Parametric; Characterization; Human; Islets

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一种有前途的选择。然而，关键的生物学和制度障碍阻碍了这种治疗策略的广泛利用。其中最主要的是无法恢复足够数量的高质量胰岛，这高度依赖于胰腺的保存。其次，缺乏与移植后功能相关的快速、准确和灵敏的移植前测试（即效价测定）限制了我们区分“健康”制剂和功能不良的制剂的能力。此外，高昂的材料和设备成本、对训练有素的人员的需求以及强制遵守 cGMP 法规，使得胰岛分离成为一项难以在每个移植计划中一致重现的技术。出于这些原因，应开发方法来提高预测胰岛制剂在移植后是否能够在受体中发挥作用的能力，并应开发区域性胰岛隔离中心网络，以最大限度地缩短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成功建立了胰岛移植计划和隔离小组。该应用的主要目标是在区域性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物功能的能力。该提案的具体目标是： 1) 基于质量、效力和功能预测因子的多参数表征，向当地胰岛研究和移植联盟以及 ICR 网络的成员分发用于移植和研究的优质人类胰岛。 2）通过三管齐下，依次优化胰腺保存、胰岛分离、分离后培养，提高胰岛制备质量。使用灵敏的评估工具，我们将首先测试基于新型营养因子的保存溶液的效果。我们还将开发在分离、培养和运输过程中最大限度地减少胰岛损伤的方法，重点是通过在分离和培养基中添加抗氧化剂以及优化培养 pH、氧张力和温度来减少 ROS 形成并恢复“正常”代谢状态。通过这项质量改进计划，我们有信心在五年内向 ICR 研究人员提供超过 2000 万个高质量胰岛，并促进其他胰岛移植计划的开发，为糖尿病社区服务。