Glycogen Synthase Kinase 3 beta in liver ischemia reperfusion injury

糖原合酶激酶3β在肝脏缺血再灌注损伤中的作用

基本信息

批准号：
10721921
负责人：
YUAN ZHAI
金额：
$ 33.98万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10721921
关键词：
5&apos -AMP-activated protein kinase Acceleration Acute Address Affect Anti-Inflammatory Agents Autophagocytosis Bone Marrow Cell Death Induction Cell Respiration Cell physiology Cells Chronic Clinical Complication Disease Down-Regulation Excision Functional disorder Generations Genes Glycogen Synthase Kinases Graft Rejection Hepatocellular Damage Heterogeneity Homeostasis Immune Immune response Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-10 Ischemia Knockout Mice Kupffer Cells Liver Liver neoplasms Macrophage Macrophage Activation Mediating Metabolic Modeling Molecular Mus Myelogenous Neutrophil Infiltration Operative Surgical Procedures Outcome Oxygen Pathogenesis Pathway interactions Patients Pattern Pattern recognition receptor Peripheral Phenotype Phosphotransferases Play Population Population Heterogeneity Primary carcinoma of the liver cells Receptor Protein-Tyrosine Kinases Recovery Regulation Reperfusion Injury Resolution Risk Factors Role Signal Transduction Stress Testing Therapeutic Time Tissues Transplantation Warm Ischemia clinically relevant design experimental study flexibility glycogen synthase kinase 3 beta immune activation immune cell infiltrate in vivo inhibitor insight ischemic injury liver inflammation liver injury liver ischemia liver transplantation new therapeutic target novel novel therapeutic intervention nutrient deprivation preservation programs receptor repair function repaired response restraint tissue injury tumor

项目摘要

Project Summary Ischemia reperfusion injury (IRI) is a major complication after liver surgery. In liver transplantation, it is a major risk factor for both acute and chronic graft rejection and restrains the use of marginal donors. Liver inflammatory immune response drives the pathogenesis of IRI. Despite the progress in studies of cellular and molecular mechanisms of the response, questions regarding to the potential distinctive roles of tissue resident vs. infiltration macrophages (iMФs), and the resolution of liver IRI remain to be defined. Glycogen synthase kinase 3β (Gsk3β) is a unique signaling kinase that it differentially regulates pro- and anti-inflammatory gene programs in MФs upon innate stimulations. It has been shown in a murine liver partial warm ischemia model that both Gsk3 inhibitors in WT hosts and myeloid Gsk3β deficiency protect livers from IRI via an AMPK- IL-10-dependent mechanism. The clinical relevance of AMPK in liver ischemia has been documented recently in hepatic tumor resection. Preliminary experiments of this proposal have found that Gsk3β also regulates the resolution of liver IRI. In fact, Gsk3β regulates liver inflammatory immune activation and resolution by targeting distinctive populations of liver MФs. KCs depletion diminished the liver protective phenotype in myeloid Gsk3β KO mice against IR. However, the recovery of liver IRI remain accelerated in these KC-depleted KO hosts, indicating that Gsk3β regulates iMФs in resolving tissue inflammation. Current proposal will dissect mechanisms of Gsk3β regulation of these two types of MФs at different stages of liver IRI. IR-induced liver inflammatory immune activation is characterized by infiltration and activation of MФs from peripheral (iMՓs), as well as necroptotic depletion and pro-inflammatory conversion of tissue resident KCs. In liver inflammation resolution, MФs repair hepatocellular damage and clear infiltrated neutrophils via Tyro3-Axl-MerTK (TAM) receptor tyrosine kinase (RTK)-mediated efferocytosis. Macrophage necroptosis and efferocytosis potently regulate their activation and differentiation. Gsk3β promotes stress-induced cell death and regulates TAM expressions in MФs. The proposal will test the hypothesis that Gsk3β regulates KC necroptosis via AMPK and pro-inflammatory immune activation via Mer RTK; and Gsk3β inhibition/inactivation facilitates iMФ conversion from pro-inflammatory to reparative type by enhancing Axl-mediated efferocytosis and immune regulatory signaling. Two specific aims are designed to address how Gsk3β regulates KC inflammatory activation, and iMФ reprogramming/functions, in the activation and resolution stages of liver IRI, respectively. Results of these experiments shall offer fresh new insight into immune regulatory functions of Gsk3β in MФs in both the activation and resolution of liver inflammation and injuries and provide rationales for novel therapeutic strategies to restore liver homeostasis in patients.

项目概要缺血再灌注损伤（IRI）是肝移植术后的主要并发症。急性和慢性移植物排斥的主要危险因素，并限制边缘供体的使用。尽管细胞和免疫反应的研究取得了进展，但炎症免疫反应仍然是 IRI 的发病机制。反应的分子机制，有关组织驻留者潜在独特作用的问题与浸润巨噬细胞 (iMФs) 相比，肝脏 IRI 的分辨率仍有待定义。糖原合酶激酶 3β (Gsk3β) 是一种独特的信号激酶，可差异性调节 pro- 在先天刺激下 MФ 中的抗炎基因程序已在小鼠肝脏中得到证实。部分热缺血模型表明，WT 宿主中的 Gsk3 抑制剂和骨髓 Gsk3β 缺陷均能保护肝脏通过 AMPK-IL-10 依赖性机制从 IRI 中获得 AMPK 在肝缺血中的临床相关性。最近在肝肿瘤切除术中的初步实验发现。 Gsk3β 还调节肝脏 IRI 的消退。事实上，Gsk3β 调节肝脏炎症免疫激活。并通过针对特定的肝脏 MФ 群体消除 KC 来消除肝脏保护作用。骨髓 Gsk3β KO 小鼠针对 IR 的表型然而，肝脏 IRI 的恢复仍然加速。这些 KC 耗尽的 KO 宿主，表明 Gsk3β 调节 iMФ 解决组织炎症。该提案将剖析 Gsk3β 在肝脏 IRI 不同阶段对这两类 MФ 的调节机制。 IR 诱导的肝脏炎症免疫激活的特点是 MФ 的浸润和激活来自外周 (iM†s) 的细胞，以及组织驻留物的坏死性耗尽和促炎性转化 KCs 在肝脏炎症消退中，MФs 通过修复肝细胞损伤并清除浸润的中性粒细胞。 Tyro3-Axl-MerTK (TAM) 受体酪氨酸激酶 (RTK) 介导的巨噬细胞坏死性凋亡和胞吞作用有效调节 Gsk3β 的激活和分化，促进应激诱导的细胞死亡。并调节 MФ 中的 TAM 表达该提案将检验 Gsk3β 调节 KC 的假设。通过 AMPK 进行坏死性凋亡，通过 Mer RTK 和 Gsk3β 进行促炎性免疫激活；抑制/失活促进 iMФ 从促炎型转化为修复型增强 Axl 介导的胞吞作用和免疫调节信号传导。两个具体目标旨在解决 Gsk3β 如何调节 KC 炎症激活和 iMФ 重编程/功能，分别在肝脏 IRI 的激活和消退阶段。实验将为 MФ 中 Gsk3β 的免疫调节功能提供全新的见解。激活和解决肝脏炎症和损伤，并为新的治疗方法提供理论基础恢复患者肝脏稳态的策略。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK.

Gsk3β 通过 MerTK 调节肝脏缺血/再灌注损伤的解决。

DOI：
发表时间：
2023-01-10
期刊：
影响因子：
8
作者：
Zhang, Hanwen;Ni, Ming;Wang, Han;Zhang, Jing;Jin, Dan;Busuttil, Ronald W;Kupiec;Li, Wei;Wang, Xuehao;Zhai, Yuan
通讯作者：
Zhai, Yuan