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
- 批准号:10268216
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-22 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAgonistAnti-Inflammatory AgentsAntiinflammatory EffectAttenuatedAutophagocytosisBindingBiologicalCell physiologyCellsChronicClinicalEpidemicFormulationGenesGlucocorticoid ReceptorGlucocorticoidsGoalsGoldHeart failureHepaticHepatic TissueHepatocyteHepatologyHomeostasisHumanImmuneInflammationInflammatoryInterventionKnock-in MouseLinkLiverLiver FibrosisLiver diseasesLiver neoplasmsMacrophage ActivationMolecularMusOrganOrgan DonorOrgan TransplantationOutcomePathologyPathway interactionsPatientsPerfusionPharmacologyPhasePhase III Clinical TrialsPhenotypePilot ProjectsPrimary carcinoma of the liver cellsPropertyPublishingReceptor SignalingRecombinantsRegulationRejuvenationRelaxinReperfusion InjuryResistanceResolutionRoleSIRT1 geneSeveritiesSignal TransductionSolidSomatomedinsStressSystemT-LymphocyteTestingTissuesTransplant RecipientsTransplantationalternative treatmentchronic liver diseaseeditorialexperimental studyglucocorticoid-induced orphan receptorimmunoregulationimprovedinnovationinsightliver ischemialiver transplantationmacrophagemimeticsnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelpeptide hormonepreservationpreventreceptorregeneration functionrelating to nervous systemrelaxin receptorresponseside effectsmall moleculestandard of caresuccesstissue injurytooltransplant model
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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$ 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:
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:
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