THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION

松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Hepatic ischemia/reperfusion injury (IRI), an innate immune-driven inflammation response, is a major obstacle limiting the success of orthotopic liver transplantation (OLT) in patients with end-stage liver disease and those with tumors of hepatic origin. Although significant progress has been made in better appreciation of the liver inflammatory cascade by IR-stress, much less is known about its resolution, which may affect not only the severity of tissue injury itself but also, more importantly, the long-term outcomes. Recent studies document striking cytoprotective functions of hrRLX (recombinant human relaxin-2) against IR-stress in mouse OLT models via hepatocyte glucocorticoid receptor (GR) signaling; while polarizing macrophage activation via Notch1 promoted IRI-OLT resistance. These experimental findings, supported by a clinical evidence of enhanced GR/Notch1 phenotype needed for IRI resistance in human OLT, prompted to propose that rhRLX may function as a novel GR agonist and glucocorticoid (GC) mimetic in liver transplantation. Pilot studies also point to anti- fibrotic functions of the cognate RXFP1 receptor, a GR-independent RLX-2 binding partner. As the conventional murine OLT model offers a limited translational utility, this project will be dissecting GR – RXFP1 molecular interplay in mice expressing human RXFP1 gene; as well as testing new concepts of RXFP1-driven hepatic rejuvenation of discarded human livers during hypothermic machine preservation. A newly discovered divergent role of GR–RXFP1 signaling axis in the “acute” and “resolution” phase of IRI-OLT inflammation, has prompted to put forth a novel and heretofore untested overall hypothesis, that: 1/ pharmacological rhRLX-induced GR enhancement will rescue OLT from acute IR-insult; while 2/ harnessing GR-independent rhRLX signaling via its cognate receptor, RXFP1, will promote homeostatic/anti-fibrotic functions in the inflammation resolution phase. Two interlocked aims explore this hypothesis: Aim 1: Delineate molecular mechanisms of rhRLX – GR hepatocellular protection in OLT (acute IRI-inflammation phase). Aim 1.1: Test hypothesis that hepatocellular Keap1-dependent Nrf2 signaling is indispensable for rhRLX – GR axis to prevent DAMPs release and innate inflammation in cold-stored donor livers. Aim 1.2: Test hypothesis that SIRT1 enhances GR-induced hepatocyte regenerative functions/autophagy in IR-stressed OLT. Aim 2. Delineate molecular mechanisms of Notch1 / RXFP1 anti-fibrotic functions in OLT (IRI-inflammation “resolution” phase). Aim 2.1: Test hypothesis that Notch1 (macrophage) – RXFP1 (T cell) cross-regulation is essential in the resolution of IRI – OLT inflammation. Aim 2.2: Test hypothesis that the activation of human RLX receptor exerts anti-fibrotic functions in the resolution of IRI-OLT inflammation in humanized RXFP1 “knockin” mouse system. Aim 2.3: Test hypothesis that activation of RXFP1 receptor during hypothermic machine preservation attenuates inflammation and rejuvenates discarded human donor livers.
项目概要/摘要 肝缺血/再灌注损伤(IRI)是一种先天免疫驱动的炎症反应,是一个主要障碍 限制了终末期肝病患者和那些患者的原位肝移植(OLT)的成功 患有肝源性肿瘤。尽管在更好地认识肝脏方面已经取得了重大进展 IR应激引起的炎症级联反应,对其解决方案知之甚少,这可能不仅影响 组织损伤本身的严重程度,更重要的是长期结果。最近的研究文件 hrRLX(重组人松弛素-2)在小鼠 OLT 模型中对 IR 应激具有显着的细胞保护功能 通过肝细胞糖皮质激素受体 (GR) 信号传导;同时通过 Notch1 极化巨噬细胞激活 促进IRI-OLT抵抗。这些实验结果得到了增强的临床证据的支持 人类 OLT 中 IRI 抗性需要 GR/Notch1 表型,提示 rhRLX 可能发挥作用 作为肝移植中的新型 GR 激动剂和糖皮质激素 (GC) 模拟物。试点研究还指出, 同源 RXFP1 受体(GR 独立的 RLX-2 结合伴侣)的纤维化功能。作为常规的 小鼠 OLT 模型提供有限的转化效用,该项目将剖析 GR – RXFP1 分子 表达人类 RXFP1 基因的小鼠中的相互作用;以及测试 RXFP1 驱动的肝脏的新概念 在低温机器保存过程中使废弃的人类肝脏恢复活力。新发现的分歧 GR–RXFP1 信号轴在 IRI-OLT 炎症“急性”和“消退”阶段的作用,提示 提出一个新颖且迄今为止未经检验的总体假设,即: 1/ 药理学 rhRLX 诱导的 GR 增强将挽救 OLT 免受急性 IR 损害; 2/通过其利用GR独立的rhRLX信号 同源受体 RXFP1 将在炎症消退阶段促进稳态/抗纤维化功能。 两个相互关联的目标探索了这一假设: 目标 1:描绘 OLT(急性 IRI 炎症)中 rhRLX – GR 肝细胞保护的分子机制 阶段)。目标 1.1:检验肝细胞 Keap1 依赖性 Nrf2 信号传导对于 rhRLX 不可或缺的假设 – GR 轴可防止冷藏供体肝脏中 DAMP 释放和先天性炎症。目标 1.2:测试 假设 SIRT1 在 IR 应激的 OLT 中增强 GR 诱导的肝细胞再生功能/自噬。 目标 2. 描绘 OLT 中 Notch1 / RXFP1 抗纤维化功能的分子机制(IRI-炎症) “解决”阶段)。目标 2.1:测试 Notch1(巨噬细胞)-RXFP1(T 细胞)交叉调节的假设 对于解决 IRI – OLT 炎症至关重要。目标 2.2:检验人类 RLX 激活的假设 受体在人源化RXFP1“敲入”中在IRI-OLT炎症消退中发挥抗纤维化功能 鼠标系统。目标 2.3:检验低温机期间 RXFP1 受体激活的假设 保存可以减轻炎症并使废弃的人类供体肝脏恢复活力。

项目成果

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Jerzy W Kupiec-Weglinski其他文献

Jerzy W Kupiec-Weglinski的其他文献

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{{ truncateString('Jerzy W Kupiec-Weglinski', 18)}}的其他基金

THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
  • 批准号:
    10101174
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
  • 批准号:
    10685284
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
  • 批准号:
    10472636
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
Innate-Adaptive Immune Interface in Liver Ischemia-Reperfusion Injury
肝脏缺血再灌注损伤中的先天适应性免疫界面
  • 批准号:
    9975698
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury
肝移植缺血/再灌注损伤中的先天适应性免疫调节
  • 批准号:
    9359428
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10328210
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
CEACAM1 Alternative Splicing in Liver Ischemia-Reperfusion Injury
CEACAM1 选择性剪接在肝脏缺血再灌注损伤中的作用
  • 批准号:
    10622462
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    9975689
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury
肝移植缺血/再灌注损伤中的先天适应性免疫调节
  • 批准号:
    9975685
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury
肝移植缺血/再灌注损伤中的先天适应性免疫调节
  • 批准号:
    9750602
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:

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