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The Role of Caspases in Warm and Cold Ischemia

Caspases 在热缺血和冷缺血中的作用

基本信息

批准号：
7918748
负责人：
Alkesh Harihar Jani
金额：
$ 13.11万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7918748
关键词：
Acute Acute Kidney Failure Allografting Antigens Apoptosis Apoptotic Applications Grants Brush Border Caspase Caspase Inhibitor Caspase-1 Cell Death Cells Cessation of life Chronic Chronic rejection of renal transplant Cryopreservation Data Development Epithelial Cells Functional disorder Gene Expression Grant Immune Sera Immunohistochemistry Incidence Inflammatory Injury Interferon Type II Interferons Interleukin-18 Ischemia Kidney Kidney Diseases Kidney Transplantation MHC Class I Genes Mediating Mediator of activation protein Messenger RNA Mitochondria Modeling Morphology Mus Necrosis Organ Organ Preservation Organ Preservation Solutions Perfusion Production Proteins Protocols documentation Publishing Reperfusion Therapy Research Personnel Role Transplantation Tubular formation Warm Ischemia base caspase-3 caspase-8 caspase-9 clinically relevant cytochrome c cytokine delayed graft function immunogenicity implantation inhibitor/antagonist interferon-alpha B interstitial mRNA Expression mouse development prevent programs receptor research study tubular necrosis

项目摘要

Delayed graft function (DGF) independently predicts reduced 1- and 5- year kidney transplant survival and contributes to the development of chronic allograft nephropathy (CAN). DGF is caused by both cold and warm ischemia. Cold ischemia occurs during both pulsatile machine perfusion and static cold storage of kidneys. This grant will focus on the pathophysiology of cold and warm ischemia and specifically the role of caspases. Caspase-3 is a major mediator of apoptotic and necrotic cell death. Caspase-1 converts the pro- inflammatory cytokines IL-1beta and IL-18 to their active forms. The overall hypothesis is that caspases mediate proximal tubular damage in both cold and warm ischemia. In a model of cold ischemia the contribution of caspase-3 to proximal tubular apoptosis as well as severe brush border injury will be assessed. Gene expression, protein and activity of caspases-3, 7, 9 (mitochondrial pathway of apoptosis) and 8 (death receptor pathway of apoptosis) will be determined during both static and pulsatile cold ischemia. Immunohistochemistry for activated caspase-3 in proximal tubules will be performed. The effect of caspase inhibition on kidney morphology will be assessed. The findings of these experiments will contribute to the understanding of cold ischemia injury and organ preservation. Caspase-1-mediated production of IL-18 mediates ischemic ARF. IL-18 is a potent inducer of interferbn gamma, which is a powerful inducer of MHC expression. Caspase-1 and IL-18-mediated increase in interferon gamma expression in the kidney and MHC expression on proximal tubules will be determined in a model of warm ischemia. Interferon gamma and MHC class I and II mRNA expression in the kidney will be assessed. The effect of caspase-1, IL-18 and interferon gamma inhibition on MHC expression will be evaluated. Reduced MHC expression is associated with decreased kidney graft immunogenicity and has important implications for the deleterious effect of DGF on both short and long-term allograft function.

移植肾功能延迟(DGF)独立预测肾移植术后1年和5年存活率下降有助于慢性移植物肾病(CAN)的发展。DGF是由寒冷和寒冷引起的热缺血。冷缺血发生在脉冲式机器灌流和静态冷藏过程中肾脏。这笔赠款将侧重于冷缺血和热缺血的病理生理学，特别是血管紧张素转换酶的作用半胱氨酸酶。Caspase-3是细胞凋亡和坏死性死亡的主要介质。Caspase-1将PRO-1 炎症细胞因子IL-1β和IL-18对其活性形式的影响。总体假设是半胱氨酸酶冷缺血和热缺血均可引起近端肾小管损伤。在一种冷缺血模型中 Caspase-3在近曲小管细胞凋亡以及严重的刷状缘损伤中的作用评估过了。Caspase-3、7、9(线粒体凋亡途径)的基因表达、蛋白及活性和8(死亡受体的细胞凋亡途径)将在静态和脉动的寒冷中被确定缺血症。将进行近端小管中活化的caspase-3的免疫组织化学检查。其效果将评估半胱氨酸氨基转移酶抑制对肾脏形态的影响。这些实验的发现将有助于对冷缺血损伤和器官保存的认识。半胱氨酸天冬氨酸蛋白酶-1介导 IL-18的产生参与了缺血性ARF的发生。IL-18是干扰素-γ的有效诱导剂，干扰素-γ是一种强大的MHC表达诱导剂。Caspase-1和IL-18介导的干扰素-γ增加将在温热模型中测定肾脏的表达和近端小管上MHC的表达缺血症。将评估干扰素γ和MHC I、II类基因在肾脏中的表达。这个将评估caspase-1、IL-18和干扰素γ抑制对MHC表达的影响。减少 MHC的表达与移植肾免疫原性降低有关，并具有重要意义 DGF对同种异体移植物短期和长期功能的有害影响。