PANCREATIC TRANSPLANTATION AND DIABETIC MELLITUS

胰腺移植和糖尿病

基本信息

批准号：
6890338
负责人：
Luca Inverardi
金额：
$ 65.96万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-05-01 至 2007-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6890338
关键词：
athymic mouse cytoprotection human tissue insulin dependent diabetes mellitus pancreas pancreatic islet function pancreatic islet transplantation technology /technique development tissue /cell culture tissue /organ preservation

项目摘要

DESCRIPTION (provided by applicant): Recent clinical trials of islet transplantation for the treatment of patients with Type 1 diabetes have shown that biological replacement of insulin producing tissue is a viable therapeutic option. Enthusiasm has been re-ignited in the scientific community by the successful results at Edmonton and at other institutions, including our own. These very promising results have also highlighted the urgent need for optimizing the use of available human islets for transplantation. In fact, it was generally required to use at least two donor pancreata to treat each recipient, and this contributes to the sizeable gap between human pancreata availability and number of patients that could potentially benefit from islet transplantation. Selected approaches to tackle and resolve this problem represent the major focus of this grant. First, strategies aimed at increasing human islet availability via the use of better organ preservation will be studied. Second, strategies aimed at preventing islet cell death during isolation and in vitro culture, as well as in the peri-transplant period, will be analyzed to ameliorate the donor-recipient ratio necessary for successful islet transplantation. It is, therefore, the central hypothesis of this grant, that implementation of strategies to improve availability, viability, and functional performance of human islet preparations will result in an increased number of successful clinical islet transplants. In this grant, we propose the following specific aims: 1) to improve the availability and quality of human pancreata utilized for islet isolation by reducing islet loss/dysfunction that occurs as a consequence of pancreas procurement/preservation; 2) to improve in vitro islet culture conditions, to maximize recovery of viable, functional human islets for transplant applications; 3) to prevent islet damage/death in the peri-transplant period by inducing islet cell cytoprotection and preventing apoptosis. Strategies to study these major aims will be based on relevant end-points, such as analysis of islet yield after isolation, following novel pancreas procurement strategies, analysis of islet cell apoptosis and necrosis in novel culture conditions, and analysis of in vitro and in vivo islet function by the use of informative models of glucose-stimulated insulin secretion and analysis of functional potency in immunodeficient rodents. Strategies to improve islet availability, viability, and functional potency will include of hypoxia during pancreas preservation, modifications of culture that allow the prevention of spontaneous death and/or functional impairment, and manipulation of islets that induce protection against noxious stimuli, such as pro inflammatory cytokines and nitric oxide, likely to be responsible for substantial islet loss in the peri-transplant period. Achievement of the proposed goals will allow us to extend islet transplantation as a therapeutic option to a large cohort of patients with Type 1 diabetes

描述（由申请人提供）：用于治疗1型糖尿病患者胰岛移植的最新临床试验表明，胰岛素产生组织的生物替代是可行的治疗选择。埃德蒙顿（Edmonton）和其他机构（包括我们自己的机构）的成功成果使热情在科学界重新点燃了热情。这些非常有前途的结果还强调了迫切需要优化使用可用的人类胰岛进行移植。实际上，通常需要使用至少两个供体胰腺来治疗每个接受者，这有助于人类胰腺可用性与可能从胰岛移植中受益的患者数量之间的巨大差距。解决和解决此问题的选定方法代表了这笔赠款的主要重点。首先，将研究旨在通过使用更好的器官保存来增加人类胰岛可用性的策略。其次，将分析旨在预防分离和体外培养以及移植期的胰岛细胞死亡的策略，以改善成功的胰岛移植所需的供体 - 复发比率。因此，这笔赠款的核心假设是，实施改善人类胰岛制剂的可用性，生存能力和功能性能的策略将导致大量成功的临床胰岛移植。在这笔赠款中，我们提出以下特定目的：1）通过减少胰岛采购/保存而导致的胰岛损失/功能障碍，以改善用于胰岛隔离的人类胰腺的可用性和质量； 2）改善体外胰岛培养条件，以最大程度地恢复可行的，功能性的人类胰岛用于移植应用； 3）通过诱导胰岛细胞保护并预防凋亡，以防止移植周期的胰岛破坏/死亡。 Strategies to study these major aims will be based on relevant end-points, such as analysis of islet yield after isolation, following novel pancreas procurement strategies, analysis of islet cell apoptosis and necrosis in novel culture conditions, and analysis of in vitro and in vivo islet function by the use of informative models of glucose-stimulated insulin secretion and analysis of functional potency in immunodeficient rodents.改善胰岛可用性，生存力和功能效力的策略将包括胰腺保存过程中缺氧，允许预防自发死亡和/或功能障碍的文化修饰，以及对诱导有害刺激的保护的胰岛的操纵，例如对促炎性细胞因子的损失，可能是对造成的，可能是对造成的损失，这可能是对造成的损失。实现拟议的目标将使我们能够将胰岛移植作为治疗选择扩展到大量1型糖尿病患者