权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

AMP Kinase Activation in Calcineurin Inhibitor Nephrotoxicity

钙调神经磷酸酶抑制剂肾毒性中的 AMP 激酶激活

基本信息

批准号：
10204706
负责人：
ROSLYN B MANNON
金额：
--
依托单位：
OMAHA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204706
关键词：
5&apos -AMP-activated protein kinase Acute Renal Failure with Renal Papillary Necrosis Adverse effects Affect Allografting Apoptosis Atrophic Autophagocytosis Biochemical Bioenergetics Biogenesis Bone Marrow Calcineurin inhibitor Caring Cellular Metabolic Process Chronic Clinical Clinical Management Complement Coupled Creatinine Cyclic AMP-Dependent Protein Kinases Cyclosporine Data Diabetic Nephropathy Dose Duct (organ) structure Epithelial Epithelial Cells Exposure to Failure Fibrosis Functional disorder Goals Graft Survival HMGB1 gene Half-Life Health Heart Histologic Homeostasis Human Immune Immunosuppression Immunosuppressive Agents In Vitro Individual Inflammation Inflammation Mediators Inflammatory Injury Injury to Kidney Intervention Kidney Kidney Diseases Kidney Failure Kidney Transplantation Laboratories Laboratory mice Lead Link Liver Lung Mediating Mediator of activation protein Medical center Metabolic Metformin Mitochondria Mus NADPH Oxidase Organ Organ Transplantation Organ failure Outcome Oxidation-Reduction Oxidative Stress Pancreas Paracrine Communication Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Pharmacology Pharmacology Study Polycystic Kidney Diseases Production Property Protein Kinase RNA Interference Reactive Oxygen Species Renal function Role Series Serum Solid Testing Therapeutic Therapeutic Agents Therapeutic immunosuppression Time Tissues Toxic effect Translations Transplant Recipients Transplantation Tubular formation United States Veterans Whole Organism adenylate kinase cell injury clinical application clinically relevant effective therapy epithelial injury exhaustion improved in vivo inflammatory marker injury and repair insight interstitial kidney cell kidney dysfunction kidney preservation knock-down mRNA Expression macrophage military veteran mitochondrial dysfunction mouse model nephrotoxicity novel novel therapeutic intervention novel therapeutics organ transplant rejection paracrine preservation prevent programs reparative capacity success

项目摘要

Solid organ transplantation necessitates the use of lifelong immunosuppression. In particular, the calcineurin inhibitors (CNIs) are utilized in nearly all transplant recipients as they are potent immunosuppressants. In kidney transplantation, the use of CNIs has led to the very low rejection rates of ~7-10% per year. However, long term graft survival has not improved substantially with their utilization, with a mean half-life of 10 years for kidney transplants. A key contributor to late graft injury is CNI-nephrotoxicity which is manifested by declining kidney function and the histological features of interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis. The mechanism by which CNI induce kidney injury and failure is multifactorial, and to date, there are no specific therapeutic strategies to mitigate this injury. The goal of this submission is to identify a novel and clinically applicable strategy to ameliorate CNI-associated kidney injury. Recently, AMP-Activated Protein Kinase (AMPK), a key regulator of cell metabolism, autophagy, and mitochondrial biogenesis, has been linked to modulating kidney injury. Further, loss of AMPK activation is associated with organ inflammation and fibrosis. We hypothesize that AMPK activation could ameliorate some of the adverse metabolic consequences in renal tubular epithelium and as a corollary, AMPK activation could be a clinically relevant intervention to mitigate long term CNI nephrotoxicity. Our study will focus on cyclosporine A (CsA), a classic CNI therapeutic agent. We will utilize a complementary series of studies, both in vitro and in vivo, using a mouse model of CsA injury that we have used successfully in our laboratory. In vitro, we will focus on renal tubular epithelium, the primary target of in vivo injury. We will study both the impact of AMPK activation as well as knock down using pharmacologic agents and silencing RNAs. Outcomes will include assessments of bioenergetics, mitochondrial function, pro-inflammatory markers and the DAMP HMGB1, and paracrine impact on macrophages and their differentiation. In vivo, we will test the impact of AMPK activation on ameliorating CsA renal injury by assessing kidney function (serum creatinine), mRNA expression of inflammatory mediators within the kidney, and biochemical, cellular and histologic assessments of injury and fibrosis. We will assess both pre-emptive inhibition as well as determine the impact of AMPK activation after established CsA nephrotoxicity. To complement these pharmacologic studies, we will also employ the novel use of AMPK 1 and 2 deficient mice. Cross-transplant studies will allow us to dissect the role of systemic versus renal expression of AMPK in injury. We believe that this comprehensive approach will provide key mechanistic insights into ameliorating or mitigating CNI nephrotoxicity. The use of a clinically relevant activator, metformin, will provide an opportunity for rapid translation into our human recipients of kidneys and other solid organ transplants.

实体器官移植需要终身使用免疫抑制剂。特别是钙调神经磷酸酶抑制剂（CNI）被用于几乎所有的移植受体，因为它们是有效的免疫抑制剂。在在肾移植中，CNI的使用导致每年约7-10%的非常低的排斥率。然而，在这方面，移植物的长期存活率并未因它们的使用而得到实质性改善，平均半衰期为10年肾脏移植晚期移植物损伤的一个关键因素是CNI肾毒性，其表现为降低肾功能和间质纤维化、肾小管萎缩和小动脉透明变性的组织学特征。的 CNI诱导肾损伤和衰竭的机制是多因素的，迄今为止，治疗策略，以减轻这种伤害。本次提交的目的是确定一种新的临床改善CNI相关肾损伤的适用策略。近年来，AMP活化蛋白激酶 AMPK是细胞代谢、自噬和线粒体生物发生的关键调节因子，调节肾损伤。此外，AMPK活化的丧失与器官炎症和纤维化相关。我们假设AMPK激活可以改善肾脏中某些不良代谢结果，因此，AMPK激活可能是一种临床相关的干预措施，长期CNI肾毒性。我们的研究将集中在环孢素A（CsA），一个经典的CNI治疗剂。我们将利用CsA损伤的小鼠模型，在体外和体内进行一系列补充研究我们已经在实验室里成功地使用了。在体外，我们将重点放在肾小管上皮细胞，体内损伤靶点。我们将研究AMPK激活的影响，以及敲低使用药理学试剂和沉默RNA。结果将包括生物能量学、线粒体功能，促炎标志物和DAMP HMGB 1，以及旁分泌对巨噬细胞及其分化在体内，我们将通过评估AMPK活化对CsA肾损伤的影响来测试AMPK活化对CsA肾损伤的改善作用。肾功能（血清肌酐），肾脏内炎症介质的mRNA表达，以及损伤和纤维化的生化、细胞和组织学评估。我们将评估双方的先发制人抑制以及确定确定CsA肾毒性后AMPK活化的影响。到作为这些药理学研究的补充，我们还将采用AMPK β 1和β 2缺陷的新用途，小鼠交叉移植研究将使我们能够分析AMPK在全身和肾脏表达中的作用，损伤我们相信，这种全面的方法将为改善或减轻CNI肾毒性。临床相关激活剂二甲双胍的使用将提供一个机会以便快速转化到我们的肾脏和其他实体器官移植的人类受体中。