Lipid Mediators in Pancreatic Islet Dysfunction

胰岛功能障碍中的脂质介质

基本信息

批准号：
8005256
负责人：
JERRY L. NADLER
金额：
$ 3.17万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-31 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8005256
关键词：
Animal Model Apoptosis Arachidonate 12-Lipoxygenase Arachidonic Acids Autoimmune Diabetes Autoimmune Process Autoimmunity Beta Cell Biological Preservation Catalytic RNA Cell Death Inhibition Cells Cessation of life Cytokine Signaling Development Diabetes Mellitus Dose Functional disorder Gene Targeting Graft Survival Human Immune Immunity Inbred NOD Mice Incidence Inflammatory Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Interleukins Islets of Langerhans Islets of Langerhans Transplantation Knockout Mice Laboratories Lead Lipid Peroxides Mediating Metabolism Methods Modality Molecular Monitor Mus Pathologic Pathway interactions Play Predisposition Process Production RNA Recurrence Resistance Rodent Role Severities Signal Pathway Signal Transduction Streptozocin Structure of beta Cell of islet Testing Time Toxic effect Transplant Recipients Wild Type Mouse cell injury computerized data processing cytokine diabetic functional improvement improved in vivo islet lipid mediator mouse model novel therapeutics prevent

项目摘要

DESCRIPTION (provided by applicant): Autoimmune-mediated pancreatic beta-cell damage is central to the development of type 1 diabetes (T1DM) and its recurrence in islet transplant recipients. Proinflammatory cytokines and lipid mediators are important contributors to beta-cell damage. We have focused on the role of arachidonic acid metabolism by 12-Lipoxygenase (12LO) in leading to immune-mediated beta-cell destruction. 12LO can be activated and induced by proinflammatory cytokines. 12LO metabolites can initiate intracellutar signaling cascades leading to beta-cell dysfunction and death. In this proposal, we will test the hypothesis that the 12LO pathway plays a key role in autoimmunity-mediated inflammatory responses leading to beta-cell inhibition and death in T1DM. The specific aims are: 1) to characterize 12LO activation and induction by proinflammatory cytokines in human islets and in insulin-releasing beta-cells. Study the role and mechanism of how the 12LO pathway mediates cytokine-induced beta-cell dysfunction and death. The particular type of 12LO in human islets will be characterized. The effect of molecular inhibition of 12LO using a ribozyme or over-expression on cytokine signaling and action will be tested. 2) to define the role of 12LO in cytokine-mediated beta-cell destruction in autoimmune diabetes. 12LO expression and lipid peroxide production will be monitored in autoimmune diabetic NOD mice. Cytokine-susceptibility and cytokine signaling processes will be determined in a 12LO-null mouse. We will also further study 12-null mouse generated on NOD background. Diabetes incidence, severeness of insulitis and cytokine effects on isolated islets will be tested. Mechanism of 12LO gene targeting reduces autoimmune beta-cell destruction will be evaluated. We will also identify the inflammatory signaling pathways disrupted upon 12LO depletion in these mice. 3) Effect of 12LO gene targeting on improving islet graft survival will be studied utilizing spontaneously diabetic NOD mice as recipients. Donor islets will be from 12LO null mice as well as the wild type mouse islets-treated with the 12LO ribozyme. Graft survival and reduction in autoimmune damage will be studied. The results from this completed proposal will advance our understanding of the inflammatory processes causing autoimmune beta-cell destruction. The findings should provide new methods to preserve beta-cell mass ultimately leading to new therapeutic modalities to prevent T1DM and improve ability to reverse T1DM using islet transplantation.

描述（由申请人提供）：自身免疫介导的胰腺 β 细胞损伤对于 1 型糖尿病 (T1DM) 的发展及其在胰岛移植受者中的复发至关重要。促炎细胞因子和脂质介质是β细胞损伤的重要贡献者。我们重点研究 12-脂氧合酶 (12LO) 花生四烯酸代谢在导致免疫介导的 β 细胞破坏中的作用。 12LO可以被促炎细胞因子激活和诱导。 12LO 代谢物可以启动细胞内信号级联反应，导致 β 细胞功能障碍和死亡。在本提案中，我们将检验以下假设：12LO 通路在自身免疫介导的炎症反应中发挥关键作用，导致 T1DM 中 β 细胞抑制和死亡。具体目标是：1) 表征人胰岛和胰岛素释放β细胞中促炎细胞因子激活和诱导的12LO。研究 12LO 通路如何介导细胞因子诱导的 β 细胞功能障碍和死亡的作用和机制。将表征人类胰岛中 12LO 的特殊类型。将测试使用核酶或过度表达对 12LO 进行分子抑制对细胞因子信号传导和作用的影响。 2) 定义 12LO 在自身免疫性糖尿病中细胞因子介导的 β 细胞破坏中的作用。将监测自身免疫性糖尿病 NOD 小鼠中的 12LO 表达和脂质过氧化物产生。将在 12LO 缺失小鼠中测定细胞因子敏感性和细胞因子信号传导过程。我们还将进一步研究在 NOD 背景下生成的 12-null 小鼠。将测试糖尿病发病率、胰岛炎的严重程度以及细胞因子对孤立胰岛的影响。将评估 12LO 基因靶向减少自身免疫 β 细胞破坏的机制。我们还将鉴定这些小鼠中 12LO 耗尽后炎症信号传导通路的破坏。 3) 将利用自发性糖尿病NOD小鼠作为受体，研究12LO基因靶向对改善胰岛移植物存活的影响。供体胰岛将来自12LO无效小鼠以及用12LO核酶处理的野生型小鼠胰岛。将研究移植物存活和自身免疫损伤的减少。这项已完成提案的结果将增进我们对导致自身免疫 β 细胞破坏的炎症过程的理解。这些发现应该提供保存β细胞量的新方法，最终导致预防T1DM的新治疗方式，并提高使用胰岛移植逆转T1DM的能力。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism.

Lisofylline 是一种新型抗炎剂，通过促进线粒体代谢来保护胰腺 β 细胞免受促炎细胞因子损伤。

DOI：
10.1210/endo.143.6.8841
发表时间：
2002
期刊：
Endocrinology
影响因子：
4.8
作者：
Chen,Meng;Yang,Zandong;Wu,Runpei;Nadler,JerryL
通讯作者：
Nadler,JerryL

Inflammation blockade improves pancreatic islet function.

炎症阻断可改善胰岛功能。

DOI：
10.1016/j.transproceed.2004.09.083
发表时间：
2004
期刊：
Transplantation proceedings.
影响因子：
0
作者：
Yang,Z;Chen,M;Carter,JD;Ellett,JD;Smith,KM;Nadler,JL
通讯作者：
Nadler,JL

Assessment of human pancreatic islets after long distance transportation.

长途运输后人类胰岛的评估。

DOI：
10.1016/j.transproceed.2004.04.075
发表时间：
2004
期刊：
Transplantation proceedings.
影响因子：
0
作者：
Yang,Z;Chen,M;Deng,S;Ellett,JD;Wu,R;Langman,L;Carter,JD;Fialkow,LB;Markmann,J;Nadler,JL;Brayman,K
通讯作者：
Brayman,K

Prevention, but not cure, of autoimmune diabetes in a NOD.scid transfer model by FTY720 despite effective modulation of blood T cells.