Improved liver function and regeneration with A20

A20 改善肝功能和再生

• 批准号: 7579583
• 负责人: CHRISTIANE FERRAN
• 金额: $ 40.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579583
• 关键词: A20 protein; Accounting; Acute; Acute Liver Failure; Adult; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Cadaver; Cell Death; Cells; Cessation of life; Chronic; Cyclin-Dependent Kinase Inhibitor; Cytokine Inducible SH2-Containing Protein; Effectiveness; Engineering; Excision; Experimental Models; Face; Feedback; Gene Expression; Genetic Transcription; Hepatectomy; Hepatic; Hepatic Mass; Hepatocyte; Human; Immune; In Situ; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Intervention; Ischemia; Life; Liver; Liver Failure; Living Donors; Maintenance; Measures; Mediating; Metabolic Control; Modeling; Molecular; Molecular Target; Mus; Natural regeneration; Necrosis; Organ; Outcome; Oxidative Stress; PPAR alpha; Pathology; Patients; Phosphorylation; Physiological; Prothrombin time assay; Recovery; Reperfusion Injury; Residual state; Resistance; Role; Signal Transduction; Small Interfering RNA; Stat3 protein; TP53 gene; Testing; Therapeutic; Time; Transaminases; Translating; Transplantation; United Network for Organ Sharing; Waiting Lists; Zinc Fingers; base; caspase-8; clinical practice; cytokine; human 53BP1 protein; improved; in vivo; knock-down; lipid metabolism; liver allograft; liver cell proliferation; liver function; liver ischemia; liver transplantation; loss of function; novel; novel therapeutics; overexpression; oxidative damage; protective effect; public health relevance; regenerative; repaired; research study; response; transcription factor

DESCRIPTION (provided by applicant): The liver has remarkable regenerative capacity, allowing recovery following injury or resection. Adequate regeneration is, however, contingent upon maintenance of a healthy residual liver mass, otherwise fulminant hepatic failure ensues. This issue is of particular importance in liver transplantation where allografts face substantial ischemic, inflammatory, and immune insults that are further exacerbated in adult living donor liver transplants using "small-for-size" liver grafts. Understanding the physiologic protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies aimed at improving outcome of liver transplantation. We have identified the 7-Zinc finger protein A20 as a critical component of the protective and regenerative responses of hepatocytes in that it protects hepatocytes from apoptosis by altering the expression of the initiator Caspase 8; safeguards hepatocytes from ischemic necrosis by limiting oxidative damage; contains hepatocyte inflammatory responses by inhibiting NFkB activation; and promotes hepatocyte proliferation by decreasing the expression of the Cyclin Dependent Kinase Inhibitor p21waf1. These "hepatoprotective" functions of A20 translate into a dramatic regenerative advantage with greatly improved survival following radical lethal hepatectomy or prolonged liver ischemia in mice. Interestingly, transcription of A20 is decreased in "small-for-size" liver grafts, likely contributing to increased damage and inadequate regeneration. We have recently unraveled novel targets for A20 in hepatocytes that may account for its beneficial effects: 1) Increases the expression of Peroxisome Proliferator-Activated Receptor alpha (PPAR1), 2) Decreases the expression of p21waf1 and 3) Enhances Signal Transducer and Activator of Transcription 3 (STAT-3) phosphorylation despite lower IL-6 levels through decreasing Suppressor of Cytokine Signaling (SOCS)-3 expression We wish to: Specific Aim 1: Decipher the molecular basis for the A20 dependent protection of hepatocytes from necrotic cell death following oxidative damage and probe the involvement of PPAR1 in mediating this effect. Specific Aim 2: Explore the molecular basis for the pro-proliferative function of A20 in hepatocytes by investigating the role of p21waf1 and IL-6/STAT-3/SOCS3 in supporting this effect. Specific Aim 3: Evaluate the impact of A20 expression in the liver upon survival and function of non- optimal liver grafts, including small-for-size liver grafts and grafts with prolonged ischemia time. Demonstrating A20's beneficial effects in our experimental models should set the basis for translating A20- based therapies into clinical practice. PUBLIC HEALTH RELEVANCE: Orthotopic liver transplantation is a life-saving measure for patients suffering from acute or chronic liver failure. However, demand exceeds organ availability by several orders of magnitude, causing a number of patients to die while on the waiting list. We have identified the A20 protein as an ideal "hepatoprotective" candidate. A20 combines anti-apoptotic, anti-necrotic, anti-inflammatory, anti-oxidative and pro-proliferative functions in hepatocytes, which translates into significant survival and regenerative advantages following radical lethal hepatectomy and severe ischemia reperfusion injury in mice. We wish to test the effectiveness of A20-based therapies in improving survival and function of sub-optimal liver grafts that are usually unsuitable for transplantation. Any beneficial effects of A20 in these models would expand the pool of liver donors and help ease the severe organ shortage in liver transplantation.

描述（由申请人提供）：肝脏具有显着的再生能力，可以在受伤或切除后恢复。然而，足够的再生取决于维持健康的残留肝脏，否则会发生暴发性肝衰竭。这个问题在肝移植中尤其重要，在肝移植中，同种异体移植面临大量的缺血，炎症和免疫损伤，这些缺血性，炎症性和免疫损伤进一步加剧了使用“小型”肝脏移植物的成年活着供体肝移植。了解保护肝细胞和促进其增殖的生理保护机制对于制定旨在改善肝脏移植结果的治疗策略至关重要。我们已经将7-锌指蛋白A20鉴定为肝细胞保护性和再生反应的关键成分，因为它通过改变启动器caspase 8的表达来保护肝细胞免受凋亡的影响；通过限制氧化损伤，保障肝细胞防止缺血性坏死；通过抑制NFKB激活，含有肝细胞炎症反应；并通过降低细胞周期蛋白依赖性激酶抑制剂p21WAF1的表达来促进肝细胞增殖。 A20的这些“肝保护剂”功能转化为巨大的再生优势，其生存后，在小鼠的根本致死性肝切除术或长时间的肝脏缺血后大大提高了生存率。有趣的是，“小”肝移植物中A20的转录减少，可能导致损害增加和再生不足。我们最近在肝细胞中阐明了A20的新型靶标，这可能解释了其有益影响：1）增加过氧化物酶体增殖物增殖物激活的受体α（PPAR1）的表达，2）降低了p21WAF1和3的表达，尽管p21WAF1和3的表达降低了通过转录3（Statip-3）的降低（Station-3）降低了p21WAF1和3的表达。细胞因子信号传导（SOCS）-3我们希望：特定目的1：破译A20依赖性保护肝细胞在氧化损伤后因坏死细胞死亡的分子基础，并探测PPAR1参与介导这种效应的肝细胞。具体目标2：通过研究P21WAF1和IL-6/Stat-3/SOCS3在支持此效果方面的作用，探索A20在肝细胞中促增殖功能的分子基础。具体目标3：评估A20表达在肝脏中对非最佳肝移植物的存活和功能的影响，包括长时间缺血时间的小尺寸肝移植物和移植物。在我们的实验模型中证明A20的有益效果应为将基于A20的疗法转化为临床实践的基础。公共卫生相关性：原位肝移植是急性或慢性肝衰竭患者的挽救生命措施。但是，需求超过了几个数量级的器官可用性，导致许多患者在等待名单上死亡。我们已经将A20蛋白确定为理想的“肝保护剂”候选者。 A20结合了肝细胞中抗凋亡，抗毒性，抗炎，抗氧化和促增殖功能，在伊斯兰大细胞中，这转化为在巨大的致命性肝切除术和严重的缺血性局部重复损伤后，它转化为显着的生存和再生优势。我们希望测试基于A20的疗法在改善通常不适合移植的亚最佳肝移植物的生存和功能方面的有效性。在这些模型中，A20的任何有益作用都将扩大肝脏供体的池，并有助于缓解肝移植中严重的器官短缺。