Mitochondrial Cytoprotection to Prevent Islet Cell Death

描述（由申请人提供）： 大量证据表明，血糖的慢性升高导致糖尿病的许多主要并发症，包括肾病、视网膜病、神经病以及大血管和微血管损伤。然而，外源性胰岛素对全身血糖的调节充其量是不可预测的，试图遵守强化血糖控制的患者发生危及生命的低血糖的风险增加。因此，维持血糖正常的目标，而没有胰腺移植带来的手术风险，最好通过胰岛移植来实现。 胰岛移植后的胰岛素依赖性通常仅在输注源自两到三个供体胰腺的胰岛后才能实现，并且由于细胞凋亡导致的胰岛细胞死亡是单供体胰岛细胞移植成功率降低的主要原因。多个供体的需求恶化了器官供应和需求之间的现有差距，并提出了一个艰巨的挑战，临床翻译胰岛移植作为1型糖尿病的治疗。 SS-31（d-Arg-Dmt-Lys-Phe-NH 2）是一种新型的细胞渗透性抗氧化肽，其在线粒体内以高水平浓缩！膜的最近显示SS-31肽抑制神经元细胞的线粒体肿胀和氧化性细胞死亡。我们对小鼠胰岛细胞的研究表明，SS-31的线粒体靶向导致：（1）胰腺的胰岛产量增加;（2）减少胰岛细胞凋亡;（3）改善糖尿病小鼠的移植后功能。 拟议的实验将在5年内进行，旨在解决胰腺回收、保存、胰岛分离和移植中的问题，这些问题会促进细胞损伤，最终导致胰岛细胞死亡。我们将通过检查SS-31对胰岛供体（具体目标1）、胰岛分离试剂（具体目标2）、体外培养（具体目标3）和胰岛移植受者（具体目标4）给药的效果，以系统的方式评价SS-31促进胰岛移植物存活的疗效。我们将检查SS-31的影响（1）胰岛细胞产量，（2）胰岛细胞凋亡，（3）胰岛线粒体功能和（4）移植后胰岛移植功能。我们期望通过系统的研究，我们将获得可用于1型糖尿病患者胰岛移植临床试验的知识。

DESCRIPTION (provided by applicant): There is considerable amount of evidence indicating that chronic elevation of plasma glucose causes many of the major complications of diabetes, including nephropathy, retinopathy, neuropathy and macro- and microvascular damage. However, the regulation of systemic blood glucose with exogenous insulin is unpredictable at best and patients attempting to abide intensive glucose control are at increased risk for the development of life threatening hypoglycemia. Therefore, the goal of euglycemic maintenance, without the surgical risks conferred by pancreas transplant, is best achieved by islet transplantation. Insulin independence following islet transplant is often attainable only after the infusion of islets derived from two to three donor pancreata and islet cell demise due to apoptosis is a major contributor to the diminished success of single donor islet cell transplants. The multiple donor requirements worsen the existing disparity between organ supply and demand and present a formidable challenge to the clinical translation of islet transplantation as a treatment for type 1 diabetes. SS-31 (d-Arg-Dmt-Lys-Phe-NH2) is a novel cell permeable anti-oxidant peptide that concentrates at high levels at the inner mitochondria! membrane. The SS-31 peptide was recently shown to inhibit mitochondrial swelling and oxidative cell death of neuronal cells. Our studies with mouse islet cells suggest that mitochondrial targeting with SS-31 results in: (1) an increase in islet yield from the pancreas; (2) reduces islet cell apoptosis; and (3) improves post transplant function in diabetic mice. The proposed experiments, to be carried out over a 5-year period, are designed to resolve issues in pancreas retrieval, preservation, islet isolation and transplantation that promote cellular injury culminating in islet cell death. We will evaluate the efficacy of SS-31 to facilitate islet graft survival in a systematic fashion, by examining its effect when administered to islet donors (Specific aim 1), to islet isolation reagents (Specific aim 2), to in-vitro culture (Specific aim 3) and to islet transplant recipients (Specific aim 4). We will examine SS-31 effects (1) islet cell yield, (2) islet cell apoptosis (3) islet mitochondrial function and (4) post transplant islet graft function. It is our expectation that as a result of our systematic investigation, we will gain knowledge translatable to the clinical islet transplantation trials in patients with type 1 diabetes.