Improved liver function and regeneration with A20

A20 改善肝功能和再生

• 批准号: 7761195
• 负责人: CHRISTIANE FERRAN
• 金额: $ 40.39万
• 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/7761195
• 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）：肝脏具有显著的再生能力，允许在损伤或切除后恢复。然而，充分的再生取决于健康的残余肝质量的维持，否则会导致暴发性肝功能衰竭。这个问题在肝移植中特别重要，其中同种异体移植物面临大量的缺血性、炎症性和免疫损伤，这些损伤在使用“小尺寸”肝移植物的成人活体肝移植中进一步加剧。了解保护肝细胞并促进其增殖的生理保护机制对于设计旨在改善肝移植结果的治疗策略至关重要。我们已经鉴定了7-锌指蛋白A20作为肝细胞保护和再生反应的关键组分，因为它通过改变起始物Caspase 8的表达来保护肝细胞免于凋亡;通过限制氧化损伤来保护肝细胞免于缺血性坏死;通过抑制NF κ B活化来抑制肝细胞炎症反应;并通过降低细胞周期蛋白依赖性激酶抑制剂p21 waf 1的表达来促进肝细胞增殖。A20的这些“肝保护”功能转化为显著的再生优势，在小鼠中，在根治性致死性肝切除术或长期肝缺血后，大大提高了存活率。有趣的是，A20的转录在“小尺寸”肝移植物中减少，可能导致损伤增加和再生不足。我们最近在肝细胞中发现了A20的新靶点，这可能是其有益作用的原因：1）增加过氧化物酶体增殖物激活受体α（PPAR 1）的表达，2）降低p21 waf 1的表达和3）尽管IL-6水平较低，但通过降低细胞因子信号传导抑制因子（SOCS）增强信号转导和转录激活因子3（STAT-3）磷酸化。3表达我们希望：具体目标1：破译A20依赖性保护肝细胞免受氧化损伤后坏死细胞死亡的分子基础，并探讨PPAR 1介导这种作用的参与。具体目标二：通过研究p21 waf 1和IL-6/STAT-3/SOCS 3在支持肝细胞中A20促增殖功能中的作用，探索A20促增殖功能的分子基础。具体目标3：评价肝脏中A20表达对非最佳肝移植物（包括小尺寸肝移植物和缺血时间延长的移植物）的存活和功能的影响。在我们的实验模型中证明A20的有益作用应该为将基于A20的疗法转化为临床实践奠定基础。公共卫生相关性：原位肝移植是急性或慢性肝功能衰竭患者的一项挽救生命的措施。然而，需求超过器官供应几个数量级，导致一些病人在等待名单上死亡。我们已经将A20蛋白鉴定为理想的“保肝”候选物。A20结合了肝细胞中的抗凋亡、抗坏死、抗炎、抗氧化和促增殖功能，这转化为小鼠在根治性致死性肝切除术和严重缺血再灌注损伤后的显著存活和再生优势。我们希望测试基于A20的疗法在改善通常不适合移植的次优肝移植物的存活率和功能方面的有效性。A20在这些模型中的任何有益作用都将扩大肝脏供体库，并有助于缓解肝移植中严重的器官短缺。