Role of SLc11a1 Gen in Warm Ischemia-Reperfusion Injury
SLc11a1 Gen 在热缺血再灌注损伤中的作用
基本信息
- 批准号:6899235
- 负责人:
- 金额:$ 10.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-06-01 至 2007-05-31
- 项目状态:已结题
- 来源:
- 关键词:Kupffer&aposs cellapoptosiscytokineenzyme linked immunosorbent assaygene expressiongene induction /repressiongenetically modified animalshistologyimmunocytochemistrylaboratory mouseliver ischemia /hypoxianeutrophilnitric oxidenuclear factor kappa betapolymerase chain reactionreperfusionsuperoxidessurgerytransaminasestumor necrosis factor alpha
项目摘要
DESCRIPTION (provided by applicant):
While improvements in surgical techniques and pharmacological interventions have improved the outcome of liver resections, hemorrhagic shock, and organ transplantation, injury, rejection and eventual organ failure due to Ischemia-reperfusion (I/R) injury continue to be common place in the clinical setting. Accordingly, the development of novel treatment modalities to prevent or minimize I/R injury would be of tremendous benefit. Substantial evidence exist to support the notion that Kupffer cells (KC) are responsible for the early-phase of I/R injury, and sets the stage for the more severe polymorphonuclear leukocyte (PMN)-mediated late-phase injury. However, mechanisms by which KC and PMNs mediate their respective phases of I/R injury are not fully understood. This is reflected in the lack of success with conventional modes of therapeutic intervention both at the experimental and clinical levels. We have identified a gene, Slc11a1, which is induced during I/R injury, and mediates the production of pro-and anti-inflammatory cytokines. Consistent with this is the reduced levels of plasma TNF-alpha observed in Slc11a1-/- mice during the early phase of liver I/R injury. Slc11a1 proposed function of the regulating iron homeostasis in KC and PMNs, and its level of expression may ultimately determine if the liver is protected from I/R injury by modulating the degree of injury during both the early- and late-phases of I/R injury. To test this hypothesis we propose three aims: (1) We will determine if disruption of the Slc11a1 gene protects the mouse liver from I/R injury. To investigate this, we will look at both the early- and late-phases of I/R injury in the mouse liver model, in vivo. Standard biochemical and histological techniques will be employed to evaluate blood transaminases and H&E liver sections, in conjunction with molecular techniques to monitor the protein and mRNA levels of Slc11a1 and pro-and anti-inflammatory cytokines. (2) We will determine if disruption of the Slc11a1 gene blunts the activation/priming of KC and infiltrating PMNs during I/R injury. Slc11a1 mediates the activation of KC and PMNs. Therefore, we will isolate these cells from livers subjected to I/R, and use standard biochemical and molecular techniques to evaluate their degree of activation/priming by looking at spontaneous superoxide anion and NO production, and NF-kappaB activation. (3) We will determine the mechanism(s) by which the Slc11a1 gene elicits activation of KC and PMNs. If disruption Slc11a1 protects the liver from I/R injury by modulating mediation of iron homeostasis, then deferoxamine pretreatment of Slc11a1+/+ mice before I/R injury should protect the liver from I/R mediated injury, as observed for Slc11a1-/- mice. Furthermore, pretreatment with Fe2SO4 should reverse the protection observed in Slc11a11-/- mice. As in Aim #1, we will assess liver injury with use of standard biochemical and histological techniques. These studies will identify molecular mechanisms by which Slc11a1 modulates liver I/R injury, and will provide a novel target for therapeutic intervention in I/R-mediated organ injury.
描述(由申请人提供):
虽然外科技术和药物干预的改进改善了肝切除、失血性休克和器官移植的预后,但由于缺血再灌注(I/R)损伤而导致的损伤、排斥反应和最终的器官衰竭在临床上仍然很常见。因此,开发新的治疗方式以预防或尽量减少I/R损伤将是非常有益的。已有大量证据支持枯否细胞(Kupffer cell,KC)是I/R损伤早期的原因,并为更严重的中性粒细胞(PMN)介导的晚期损伤奠定了基础。然而,KC和PMN调节其各自的I/R损伤阶段的机制尚不完全清楚。这反映在传统的治疗干预模式在实验和临床层面上都缺乏成功。我们已经确定了一个基因SLc11a1,它在I/R损伤过程中被诱导,并介导促炎和抗炎细胞因子的产生。与此一致的是,在肝脏I/R损伤的早期阶段,SLc11a1/-小鼠观察到血浆肿瘤坏死因子-α水平降低。SLc11a1提出了KC和PMN中铁稳态的调节作用,其表达水平可能最终决定了肝脏是否通过调节I/R损伤的早期和晚期的损伤程度来保护肝脏免受I/R损伤。为了验证这一假设,我们提出了三个目标:(1)我们将确定SLc11a1基因的破坏是否能保护小鼠肝脏免受I/R损伤。为了研究这一点,我们将在活体内观察小鼠肝脏模型中I/R损伤的早期和晚期。将使用标准的生化和组织学技术来评估血液转氨酶和H&E肝切片,并结合分子技术来监测SLc11a1以及促炎和抗炎细胞因子的蛋白质和mRNA水平。(2)我们将确定破坏Slc11a1基因是否会在I/R损伤过程中钝化KC的激活/启动和PMN的渗透。SLc11a1介导KC和PMN的激活。因此,我们将从I/R的肝脏中分离出这些细胞,并使用标准的生化和分子技术通过观察自发的超氧阴离子和NO的产生以及NF-kappaB的激活来评估它们的激活/启动程度。(3)探讨SLc11a1基因激活KC和PMN的机制(S)。如果阻断Slc11a1通过调节铁稳态的调节来保护肝脏免受I/R损伤,那么在I/R损伤之前对Slc11a1+/+小鼠进行去铁胺预处理应该可以保护肝脏免受I/R介导的损伤,就像在Slc11a1-/-小鼠中观察到的那样。此外,Fe2SO4预处理应逆转在SLc11a11-/-小鼠中观察到的保护作用。正如目标1所示,我们将使用标准的生化和组织学技术来评估肝脏损伤。这些研究将确定SLc11a1调节肝脏I/R损伤的分子机制,并将为I/R介导的器官损伤的治疗干预提供一个新的靶点。
项目成果
期刊论文数量(0)
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SAMUEL WYLLIE其他文献
SAMUEL WYLLIE的其他文献
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{{ truncateString('SAMUEL WYLLIE', 18)}}的其他基金
Role of SLc11a1 Gen in Warm Ischemia-Reperfusion Injury
SLc11a1 Gen 在热缺血再灌注损伤中的作用
- 批准号:
6747380 - 财政年份:2003
- 资助金额:
$ 10.76万 - 项目类别:
Role of SLc11a1 Gen in Warm Ischemia-Reperfusion Injury
SLc11a1 Gen 在热缺血再灌注损伤中的作用
- 批准号:
6618611 - 财政年份:2003
- 资助金额:
$ 10.76万 - 项目类别:
Role of SLc11a1 Gen in Warm Ischemia-Reperfusion Injury
SLc11a1 Gen 在热缺血再灌注损伤中的作用
- 批准号:
7272439 - 财政年份:2003
- 资助金额:
$ 10.76万 - 项目类别:
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