HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation

HuR/HIF – SIRT1 信号轴在肝移植复兴中的作用

• 批准号: 10211459
• 负责人: Jerzy W Kupiec-Weglinski
• 金额: $ 46.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211459
• 关键词: Acute; Address; Anti-Inflammatory Agents; Antigens; Biological Markers; Biopsy Specimen; Chronic; Clinical; Coculture Techniques; Cytoprotection; DNA-Binding Proteins; Deacetylase; Depressed mood; Enzymes; Feedback; Genetic Transcription; Goals; Gold; HIF1A gene; Hepatic; Hepatic Tissue; Hepatocyte; Homeostasis; Human; Hydrogen Peroxide; Hypersensitivity; Hypoxia; Hypoxia Inducible Factor; ITGAM gene; Immune; Inflammation; Inflammatory Response; Intervention; Ischemia; Laboratories; Lead; Life; Link; Liver; Liver diseases; Liver neoplasms; Macrophage Activation; Mediating; Mediator of activation protein; Messenger RNA; Mus; Myelogenous; Natural Immunity; Organ; Organ Donor; Organ Transplantation; Outcome; Oxidative Stress; Pathway interactions; Patients; Perfusion; Pharmacology; Proteins; Recovery; Regulation; Rejuvenation; Reperfusion Injury; Reperfusion Therapy; Resistance; Resveratrol; SIRT1 gene; Savings; Signal Transduction; Solid; Sterility; Stress; System; Temperature; Testing; Therapeutic; Tissues; Transgenic Model; Translating; Transplant Recipients; Transplantation; bench to bedside; biological adaptation to stress; cell growth regulation; cell injury; clinically relevant; conditioning; cytokine; delayed graft function; experience; experimental study; improved; improved functioning; in vitro Model; inhibitor/antagonist; innovation; liver biopsy; liver function; liver injury; liver ischemia; liver transplantation; macrophage; mouse model; novel; preconditioning; preservation; programs; reconstitution; response; standard of care; success; synergism; transplant model

ABSTRACT Orthotopic liver transplantation (OLT) is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin. However, the scarcity of donor organs prompted the use of extended criteria “marginal” livers, which are particularly susceptible to ischemia-reperfusion injury (IRI), which predispose to acute/chronic rejection, and may require re-transplantation. We have introduced the concept of organ “rejuvenation”, i.e., conversion of the donor liver from the state of IRI-hypersensitivity to the homeostatic state of IRI-resistance. We have also proposed that SIRT1 deacetylase serves as a rheostat linking IR-stress with liver rejuvenation in both, mouse and human OLT. We have recently identified new regulators of hepatic resistance against warm vs. cold ischemia stress responses, i.e., Human Antigen R (HuR) and Hypoxia-Inducible Factor (HIF-1α). We have also discovered Ikaros (IKZF1), acts as a macrophage activation marker and exacerbates liver IRI. Importantly, we also found that preserved hepatocellular function/improved clinical outcomes in human OLT patients were associated with increased HuR/HIF-1α but depressed Ikaros levels in the liver biopsy samples. We hypothesize that crosstalk between hepatocyte HuR / HIF-1α and macrophage Ikaros provides a new means to regulate the adaptation of donor livers to IR-stress and reperfusion-mediated hepatic damage. Specific Aim 1: Determine mechanisms of hepatocyte HuR / HIF-1α crosstalk with SIRT1 in IRI-OLT. Hypothesis: Hepatocyte SIRT1 activation, controlled by distinct hypoxia/reoxygenation (H/R) requirements for HuR (warm H/R) vs. HIF-1α (cold H/R), provide new means to regulate adaptation of donor livers to IR-stress. 1.1: SIRT1 function is dependent on HuR signaling for anti-inflammatory responses in oxidative stress. 1.2: HuR/HIF-1α signaling in a mouse model of hepatic ischemia is temperature stress-dependent. 1.3: HIF-1α controls cold-induced IRI-OLT. 1.4: HuR controls warm-induced IRI-OLT. Specific Aim 2: Delineate mechanisms of macrophage Ikaros crosstalk with SIRT1 in IRI-OLT. Hypothesis: Macrophage Ikaros signaling exacerbates IRI-OLT by repressing SIRT1 transcription and M2 macrophage polarization. 2.1: Ikaros-SIRT1 myeloid axis influences hepatic HuR/HIF1α hypoxia sensing circuit in IRI-OLT. 2.2: Macrophage Ikaros signaling depends on SIRT1 transcription for M2 polarization. Specific Aim 3: Define mechanism of human liver rejuvenation under hypothermic machine preservation. Hypothesis: Manipulation of HIF-1α / SIRT1 axis during ex-vivo HMP improves hepatocellular function to rejuvenate human livers declined for transplantation due to preexisting poor quality. 3.1: Pharmacological stabilizer of HIF-1α protein synergizes with SIRT1 to improve human liver function. 3.2: Preconditioning with PHD-inhibitor, which activates/stabilizes HIF-1α, synergizes with enhanced SIRT1 signaling to ameliorate inflammation, promote cytoprotection, and rejuvenate human livers. These experiments are of high relevance to refine donor liver donation (DBD and DCD) as well as to improve quality/size of the current organ supply.

抽象的 原位肝移植（OLT）是末期肝病和 那些具有肝脏起源肿瘤的人。但是，捐赠者器官的稀缺性促使使用了扩展条件 “边际”生命，特别容易受到缺血 - 重新灌注损伤（IRI），易于 急性/慢性排斥，可能需要重新置换。我们介绍了器官的概念 “恢复活力”，即，从伊利 - 激烈的状态转化为供体肝脏到稳态状态 伊利抗性。我们还建议SIRT1脱乙酰基酶用作连接IR应力与肝脏的变阻器 小鼠和人类OLT的恢复活力。我们最近确定了肝炎抗性的新调节剂 反对温暖与冷缺血应力反应，即人类抗原R（HUR）和缺氧诱导因子 （HIF-1α）。我们还发现了ikaros（ikzf1），充当巨噬细胞激活标记和恶化 肝脏IRI。重要的是，我们还发现保留的肝细胞功能/改善了人类的临床结果 OLT患者与HUR/HIF-1α的增加有关，但拒绝了肝活检中的Ikaros水平 样品。我们假设肝细胞HUR / HIF-1α与巨噬细胞之间的串扰提供了一个 调节捐赠者生活的新方法，以减轻压力和再灌注介导的肝损害。 具体目标1：确定与iri-olt中SIRT1的肝细胞HUR / HIF-1α串扰的机制。 假设：肝细胞SIRT1激活，受独特的低氧/re氧（H/R）的控制 HUR（温暖的H/R）与HIF-1α（冷H/R），提供了调节捐赠者生活的新方法，以适应IR-Surs Press。 1.1：SIRT1函数取决于氧化应激中抗炎反应的HUR信号传导。 1.2： 肝缺血小鼠模型中的HUR/HIF-1α信号传导是温度应力依赖性的。 1.3：HIF-1α 控制冷诱导的iri-olt。 1.4：HUR控制热诱导的Iri-olt。 具体目标2：描述巨噬细胞Ikaros与SIRT1在iri-olt中串扰的机制。 假设：巨噬细胞ikaros信号通过抑制SIRT1转录和M2加剧了iri-olt 巨噬细胞极化。 2.1：ikaros-sirt1髓样轴影响肝炎HUR/HIF1α缺氧感应电路 在iri-olt。 2.2：巨噬细胞Ikaros信号取决于M2极化的SIRT1转录。 特定目的3：定义在低温机器保存下人类肝修订的机制。 假设：在EX-VIVO HMP期间操纵HIF-1α / SIRT1轴可将肝细胞功能提高到 恢复活力的人类生命因质量较差而因移植而下降。 3.1：药理 HIF-1α蛋白的稳定剂与SIRT1协同作用，以改善人肝功能。 3.2：与 激活/稳定HIF-1α的PHD抑制剂与增强的SIRT1信号协同为改善 炎症，促进细胞保护并恢复了人类的生命。这些实验与 精炼供体肝捐赠（DBD和DCD），以及提高当前器官供应的质量/大小。