siRNA Protection of Composite Islet Kidney Transplant in Baboons

狒狒复合胰岛肾移植的 siRNA 保护

基本信息

批准号：
8970851
负责人：
ANNA MOORE
金额：
$ 59.27万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8970851
关键词：
Affect Allogenic Animals Apoptosis Apoptotic Autologous Blood Child Clinical Diabetes Mellitus Diabetic Nephropathy End stage renal failure Engraftment Evaluation Event Family suidae Gene Silencing Gene Targeting Genes Goals Graft Survival Hepatotoxicity Histology Homologous Transplantation Hyperglycemia Hypoxia Image Immunologics Inbreeding Induction of Apoptosis Inflammatory Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Kidney Diseases Kidney Failure Kidney Part Kidney Transplantation Label Lead Liver Living Donors Magnetic Resonance Imaging Magnetic nanoparticles Magnetism Mediating Mediator of activation protein Miniature Swine Modeling Monitor Outcome Pancreas Pancreatectomy Papio Preparation Procedures Protocols documentation Reaction Renal Glycosuria Renal function Reporter Reverse Transcriptase Polymerase Chain Reaction Risk Small Interfering RNA Staging Technology Time Toxic effect Transplant Recipients Transplantation Vascularization Western Blotting capsule caspase-3 caspase-8 clinical application diabetic diabetic patient imaging probe improved in vitro testing in vivo iron oxide islet mouse model nanoparticle new technology nonhuman primate pre-clinical public health relevance restoration theranostics therapeutic siRNA type I diabetic uptake

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to combine two novel technologies in order to improve the capacity of pancreatic islet transplants to cure type 1 diabetes. The first technology involves transplantation of vascularized islets in the form of composite islet-kidneys (IK), which has the capacity to cure both diabetes and renal failure in swine and baboon model as we have recently demonstrated. In this protocol, pancreatic islets obtained after partial pancreatectomy are first transplanted under the autologous kidney capsule to allow for re- vascularization, and then the composite islet-kidney is transplanted in a recipien diabetic animal. Though composite autologous IK technology substantially reduces the extent of graft damage due to immunologic events, there is still considerable islet loss in IK composite due to hypoxia and ischemic loss ultimately requiring a 70% pancreatectomy of the living donor. To improve IK composite survival and significantly reduce the number of donor islets we propose to use the second technology that utilizes theranostic magnetic nanoparticles as carriers for siRNA, which upon accumulation in islet cells could silence genes responsible for islet damage prior to IK creation. In addition to serving as siRNA carriers these theranostic nanoparticles could be used as in vivo magnetic resonance imaging (MRI) reporters providing information about graft volume longitudinally and non-invasively. We have previously shown the applicability of this technology for improving graft survival in a mouse model of transplantation. In this application we propose to investigate pre-clinical utility of this approach in non-human primates by delivering siRNA-nanoparticle probes targeting genes implicated in apoptosis to islets prior to creating the IK composite. Specifically, we will target caspase 3, caspase 8 and Fas, alone or in combination, as the most important mediators of apoptosis. In vivo MR imaging will be used to monitor autologous IK graft volume followed by continuous imaging of the IK transplant in recipient diabetic animals since magnetic nanoparticles are retained in the islets long term. We expect that by targeting apoptotic genes we will reduce the damage to the islets in autologous IK composite and as a consequence will reduce the number of donor islets required for IK composite to correct hyperglycemia in diabetic recipients. By further minimizing the amount of excised pancreas and non-invasive assessment of islets volume by the MN-siRNA technology, the clinical applicability of this procedure will be more favorable for living donor IK transplantation.

描述（由适用提供）：该提案的总体目标是结合两种新型技术，以提高胰岛移植对治愈1型糖尿病的能力。第一项技术涉及以复合胰岛kidneys（IK）形式移植血管化的胰岛，该胰岛（IK）具有治愈猪和狒狒模型中糖尿病和肾衰竭的能力。在该方案中，首先将部分胰腺切除术后获得的胰岛在自体肾囊下移植，以允许再血管化，然后复合胰岛 - 基德尼在受体糖尿病动物中移植。尽管复合自体IK技术大大降低了由于免疫事件而引起的移植物损害程度，但由于缺氧和缺血性损失，IK复合材料仍然存在相当大的胰岛损失，最终需要70％的活体供体胰腺切除术。为了提高IK复合材料的存活率，并显着减少了我们建议使用第二种技术利用Theranostic磁性纳米颗粒作为siRNA的载体的供体胰岛的数量，在胰岛细胞中积累后，它们可能会在IK产生之前静音，从而使胰岛损害造成损害。除作为siRNA载体外，这些静脉纳米颗粒还可以用作体内磁共振成像（MRI）记者，可纵向和非侵入性地提供有关移植体积的信息。我们先前已经显示了该技术在移植小鼠模型中改善晶粒存活的适用性。在此应用中，我们建议通过在创建IK复合材料之前将siRNA-纳米颗粒的问题靶向隐含于胰岛的基因，以研究这种方法在非人类隐私中的临床前实用性。具体而言，我们将单独或组合靶向caspase 3，caspase 8和FAS，作为凋亡的最重要介体。体内MR成像将用于监测自体IK移植体积，然后在受体糖尿病动物中连续成像IK移植，因为长期保留了磁性纳米颗粒。我们预计，通过靶向凋亡基因，我们将减少自体IK复合材料中胰岛的损害，因此，将减少IK复合材料所需的供体胰岛数量，以纠正糖尿病接受者中高血糖症。通过进一步最大程度地减少MN-SIRNA技术对胰岛数量的卓越胰腺和非侵入性评估，该程序的临床适用性将更有利，对活生生的捐助者IK移植更有利。