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:10101174
- 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 hormonepreservationpreventreceptorregenerativerelating 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.
项目摘要/摘要
肝脏缺血/再灌注损伤(IRI)是一种先天免疫驱动的炎症反应,是一种主要障碍
限制终末期肝病患者原位肝移植(OLT)的成功
患有肝源性肿瘤。尽管在更好地了解肝脏方面已经取得了重大进展
IR应激引起的炎性级联反应,对其消退知之甚少,这可能不仅影响
不仅是组织损伤本身的严重程度,更重要的是长期结果。最新研究文献
重组人松弛素-2对小鼠原位肝移植模型IR应激的保护作用
通过肝细胞糖皮质激素受体(GR)信号;而通过Notch1极化巨噬细胞激活
增强了对IRI-OLT的抗性。这些实验发现,得到了增强的临床证据的支持
人原位肝移植IRI抵抗所需的GR/Notch1表型提示rh RLX可能发挥作用
作为一种新的GR激动剂和糖皮质激素(GC)模拟物在肝移植中的应用。试点研究也指出了反
同源RXFP1受体的纤维化功能,它是一种非GR依赖的RLX-2结合伙伴。作为传统的
小鼠原位肝移植模型提供的翻译功能有限,本项目将解剖GR-RXFP1分子
在表达人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废弃的人类肝脏的复壮。一种新发现的发散型
GR-RXFP1信号轴在IRI-OLT炎症的“急性期”和“缓解期”中的作用
提出一个新的、迄今为止未经检验的总体假设,即:1/药理学上的重组人RLX诱导GR
增强功能将使OLT免于急性IR损伤;同时通过ITS利用不依赖GR的rhRLX信号
同源受体RXFP1将在炎症消退阶段促进体内平衡/抗纤维化功能。
两个相互关联的目标探索了这一假设:
目的1:探讨重组人RLX-GR在肝移植中保护肝细胞的分子机制
阶段)。目的1.1:假设肝细胞Keap1依赖的Nrf2信号对重组人RLX是不可或缺的
-GR轴,防止冷藏供体肝脏中的湿气释放和先天炎症。目标1.2:测试
假设SIRT1增强IR应激原位肝移植中GR诱导的肝细胞再生功能/自噬。
目的2.阐明Notch1/RXFP1在原位肝移植(IRI-炎症)中抗纤维化作用的分子机制
“解决”阶段)。目的2.1:测试假设Notch1(巨噬细胞)-RXFP1(T细胞)交叉调节是
对IRI-OLT炎症的消退至关重要。目标2.2:检验假设人类RLX的激活
受体在人源化RXFP1“敲门”的IRI-OLT炎症消退中的抗纤维化作用
鼠标系统。目的2.3:测试假设RXFP1受体在低温机械过程中被激活
保存可以减轻炎症,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)
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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:
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:
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:
10268216 - 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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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
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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
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