The role of XIAP during cold ischemia and kidney transplantation.

XIAP 在冷缺血和肾移植中的作用。

• 批准号: 8360878
• 负责人: Alkesh Harihar Jani
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360878
• 关键词: Affinity; Apoptosis; Applications Grants; Binding; Brush Border; Caspase; Caspase Inhibitor; Cells; Clinical; Contralateral; Creatinine; Data; Development; Down-Regulation; End stage renal failure; Epithelial Cells; Failure; Family suidae; Functional disorder; Future; Goals; Grant; HTRA2 gene; Hour; Human; Immunofluorescence Immunologic; Injury; Ischemia; Kidney; Kidney Transplantation; Mammals; Measures; Mediating; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Organ; Pathway interactions; Protein Family; Protein Inhibition; Protein Overexpression; Proteins; Protocols documentation; Public Health; Publishing; Renal function; Risk Factors; Role; Serine Protease; Serum; Small Interfering RNA; Spermophilus; Squirrel; Time; Transplantation; Tubular formation; Up-Regulation; Western Blotting; caspase-3; cytochrome c; delayed graft function; graft function; human BIRC4 protein; improved; inhibitor-of-apoptosis protein; inhibitor/antagonist; interest; member; mouse model; novel; overexpression; prevent; protein expression

DESCRIPTION (provided by applicant): Kidney transplantation is the treatment of choice for End-Stage Renal Disease. Failure of a kidney to function after transplantation is referred to as Delayed Graft Function (DGF).DGF occurs in up to 50% of primary deceased-donor renal transplants in the US and independently predicts reduced 1- and 5-year kidney transplant survival. Prolonged cold ischemia (CI) is a significant risk factor for DGF. The average CI of donor kidneys in the US is 24 hours. DGF increases substantially when CI exceeds 30 hours. CI occurs when the organ is cooled to 4C prior to transplant, and is associated with apoptosis of renal tubular epithelial cells (RTEC). RTEC apoptosis in the donor kidney before transplant predicts the occurrence of DGF after transplant. Our published data indicates that CI of 48 hours results in increased caspase-3 protein, RTEC apoptosis and Brush Border Injury (BBI). Mammalian hibernators, such as the 13-lined ground squirrel, employ unique methods of protection that enable them to endure several days of CI during winter. We used hibernating 13-lined ground squirrels to discover novel pathways that we could study in mice. Our preliminary data indicates that hibernating 13-lined ground squirrels do not have increased caspase-3 or RTEC apoptosis despite enduring CI with a CBT of 4C for several days (far longer than that tolerable by human and mouse kidneys) (Jani 2011, in press). Protection from apoptosis in hibernating 13-lined ground squirrels is associated with upregulation of X-linked inhibitor of apoptosis protein (XIAP). This led us to measure XIAP in mice and pig kidneys subjected to CI. Our preliminary data indicates that CI of non-hibernating mouse and pig kidneys is associated with decreased XIAP, increased capsase-3 and RTEC apoptosis. A specific goal of this grant is to determine the role of XIAP in the pathophysiology of CI-induced injury in mouse kidneys. XIAP belongs to the Inhibitor of Apoptosis Protein (IAP) family, whose members bind and inhibit caspases 3, 7, and/or 9. XIAP is inhibited by a serine protease HTRA2, which in turn can be chemically inhibited by UCF-101. A specific goal of this grant is to determine the effect of CI on XIAP protein expression in mouse kidneys during CI and kidney transplantation. Specific Aim 1 investigates the effect of XIAP up-regulation (by UCF-101) and down- regulation (by HTRA2), on RTEC apoptosis. Specific Aim 2 investigates whether reducing RTEC apoptosis by manipulation of XIAP during CI before kidney transplant, improves graft function after transplant. PUBLIC HEALTH RELEVANCE: Kidney transplantation is the treatment of choice for End-Stage Renal Disease. Failure of a kidney transplant to function is referred to as Delayed Graft Function, which occurs in up to 50% of kidney transplants in the US and is a public health concern. This project investigates the role of X-liked inhibitor of apoptosis protein in the pathophysiology of Delayed Graft Function.

描述（由申请人提供）：肾脏移植是终末期肾脏疾病的选择治疗。肾脏在移植后的功能失败称为延迟移植功能（DGF）.DGF在美国最多50％的原发性死者肾移植物中发生，并独立预测1年和5年的肾脏移植存活率降低。长时间冷缺血（CI）是DGF的重要危险因素。美国供体肾脏的平均CI为24小时。当CI超过30小时时，DGF大大增加。当器官在移植前冷却至4C时，发生CI，并且与肾小管上皮细胞的凋亡有关（RTEC）。移植前供体肾脏中的RTEC凋亡预测移植后DGF的发生。我们已发布的数据表明，48小时的CI导致caspase-3蛋白，RTEC凋亡和刷边界损伤（BBI）增加。哺乳动物的冬眠（例如13层的地松鼠）采用独特的保护方法，使他们能够在冬季忍受几天的CI。我们使用冬眠的13层地松鼠发现可以在小鼠中研究的新型途径。我们的初步数据表明，尽管CASPASE-3或RTEC凋亡的冬眠并未增加，尽管CI持续了几天的CI（远比人类和小鼠肾脏可容忍的）（在2011年Jani 2011，press）。免受冬眠13层的松鼠的凋亡的保护与X线连接抑制剂的凋亡蛋白（XIAP）的上调有关。这导致我们在接受CI的小鼠和猪肾脏中测量XIAP。我们的初步数据表明，非释放小鼠和猪肾脏的CI与XIAP降低，Capsase-3和RTEC凋亡增加有关。该赠款的一个具体目标是确定XIAP在小鼠肾脏中CI诱导损伤的病理生理学中的作用。 XIAP属于凋亡蛋白（IAP）家族的抑制剂，其成员的结合并抑制caspase 3、7和/或9。XIAP受到丝氨酸蛋白酶HTRA2的抑制，而UCF-101可以化学抑制。该赠款的一个具体目标是确定CI对CI和肾移植期间小鼠肾脏中小鼠蛋白表达的影响。具体目标1研究了XIAP上调（由UCF-101）和下调（由HTRA2）对RTEC凋亡的影响。具体目标2研究了肾移植前CI操纵XIAP是否会减少RTEC凋亡，从而改善移植后的移植功能。 公共卫生相关性：肾脏移植是终末期肾脏疾病的选择。肾脏移植对功能的失败被称为延迟的移植功能，在美国多达50％的肾脏移植物中发生，这是一个公共卫生的问题。该项目调查了X类细胞凋亡蛋白抑制剂在延迟移植功能的病理生理学中的作用。