A20 Gene Polymorphisms in LDLT

LDLT 中的 A20 基因多态性

• 批准号: 8103756
• 负责人: CHRISTIANE FERRAN
• 金额: $ 26.1万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103756
• 关键词: A20 protein; Acute; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Autoimmune Diseases; Biological Markers; Biopsy; Cadaver; Chronic; Clinic; Clinical; Coagulation Process; Data; Databases; Development; Engraftment; Enrollment; Enzymes; Excision; Experimental Animal Model; Financial cost; Functional disorder; Funding Opportunities; Gene Targeting; Genes; Genetic Polymorphism; Harvest; Hepatectomy; Hepatic; Hepatocyte; Heterozygote; Hospital Costs; Hour; Human Genome; Immunohistochemistry; Incidence; Inflammatory; Interleukin-6; Intervention; Length of Stay; Life; Liver; Liver Failure; Liver Regeneration; Living Donor Liver Transplantation; Living Donors; Measurement; Measures; Messenger RNA; Metabolic Control; Morbidity - disease rate; Mus; Natural regeneration; Operative Surgical Procedures; Organ; Outcome; Partial Hepatectomy; Patients; Peripheral Blood Mononuclear Cell; Physiological; Postoperative Period; Predisposition; Prognostic Marker; Proteins; Prothrombin time assay; Recovery; Regimen; Reperfusion Injury; Reperfusion Therapy; Research Design; Research Personnel; Resistance; Risk; Role; Scheme; Scientist; Secure; Serum; Single Nucleotide Polymorphism; Solutions; Surgeon; TNF gene; Testing; Therapeutic; Three-dimensional analysis; Time; Tissues; Translations; Transplantation; United Network for Organ Sharing; Validation; Waiting Lists; Work; base; cohort; conditioning; cytokine; detector; genome wide association study; improved; liver cell proliferation; liver function; liver ischemia; liver transplantation; loss of function; novel therapeutics; overexpression; prevent; prognostic; prospective; radiologist; reconstruction; research study; response; response to injury; success; tool

DESCRIPTION (provided by applicant): Our longstanding work demonstrates that A20 (tnfaip3) enhances the liver's combined anti-inflammatory, anti- apoptotic, and anti-oxidant response to injury, and promotes hepatocyte proliferation and liver regeneration. In experimental animal models, we have shown that overexpression of A20 in the liver is protective following radical lethal hepatectomy and severe liver ischemia reperfusion injury, and allows for successful engraftment of marginal liver transplants. Loss-of-function experiments further confirmed the essential physiologic role of A20 in supporting liver regeneration. Indeed, we showed that partial A20 knockdown, as seen in heterozygote mice (A20 ) significantly impairs liver regeneration and increases lethality following 2/3 partial hepatectomy. Recently, in human genome-wide association studies, tnfaip3 gene polymorphisms have been identified as susceptibility loci for several inflammatory and autoimmune diseases. In this proposal, we wish to determine whether A20 gene polymorphisms and the expression level of A20 and of its target genes in the graft could serve as reliable prognostic markers for liver regeneration and function in living donor liver transplantation (LDLT). LDLT has emerged as a solution to ease the shortage of organs available for orthotopic liver transplantation (OLT). However its widespread use in adults is limited by the size of the graft that can be safely harvested. Biomarkers that would limit the risk to the donor while improving graft success are direly needed to allow for safe expansion of the field, which would help in easing the severe shortage of organs that are available for OLT. We plan to: 1. Probe for tnfaip3 gene polymorphisms in all living liver donors. 2. Evaluate the expression levels of A20 and of its target genes in liver transplant biopsies before liver transplantation, and in the prospective cohort of patients, after reperfusion (recipient), or before the end of surgery (donor). As part of this aim, we will also determine A20 mRNA and protein levels using peripheral blood mononuclear cells from the donor. 3. Measure circulating levels of priming cytokines (TNF and IL-6) in recipient and donor sera before and after graft reperfusion (recipient) or liver resection (donor). 4. Correlate tnfaip3 gene polymorphisms, A20 expression levels, and expression levels of its target genes with circulating levels of priming cytokines, and regeneration status, as determined by Dynamic Contrast Enhanced Multi-Detector CT (DCE-MDCT) with subsequent qualitative and quantitative 3D analysis and MeVis reconstruction, liver function (liver enzymes, and coagulation tests), and early clinical outcomes (time to discharge, primary dysfunction, need for re-transplantation). Data gathered in this work will promote the use of A20 gene polymorphisms and expression levels as reliable selection markers for pairing donors and recipients in LDLT to reduce donor morbidity and improve recipient outcomes. PUBLIC HEALTH RELEVANCE: Orthotopic liver transplantation (OLT) is a life-saving measure for patients suffering from acute or chronic liver failure. However, demand greatly exceeds organ availability, causing a number of patients to die while on the waiting list. Living donor liver transplantation (LDLT) has emerged as a solution to ease the shortage in organs that are available for OLT. However, in adults, LDLT is limited by the size of the graft that can be safely harvested. Expression levels and function of the hepatoprotective protein A20, as determined by tnfaip3/A20 gene polymorphisms, are promising tools that can be used as selection biomarkers for pairing donors and recipients in LDLT, which would reduce donor morbidity and improve recipient outcomes. Validation of A20 as a reliable prognostic biomarker in LDLT could serve as an objective measure of donor adequacy and could help to expand the field of LDLT, split livers and OLT in general.

描述（由申请人提供）：我们长期的工作证明A20（tnfaip 3）增强肝脏对损伤的联合抗炎、抗凋亡和抗氧化反应，并促进肝细胞增殖和肝再生。在实验动物模型中，我们已经表明，A20在肝脏中的过表达是保护性的根治性致死性肝切除术和严重的肝脏缺血再灌注损伤，并允许成功植入边缘肝移植。功能丧失实验进一步证实了A20在支持肝再生中的重要生理作用。事实上，我们发现部分A20基因敲除，如杂合子小鼠（A20）中所见，显著损害肝再生，并增加2/3部分肝切除术后的致死率。最近，在人类全基因组关联研究中，tnfaip 3基因多态性已被确定为几种炎症和自身免疫性疾病的易感位点。在这个建议中，我们希望确定A20基因多态性和A20及其靶基因在移植物中的表达水平是否可以作为活体肝移植（LDLT）中肝再生和功能的可靠预后标志物。LDLT已成为缓解原位肝移植（奥尔特）可用器官短缺的解决方案。然而，它在成人中的广泛使用受到可以安全收获的移植物大小的限制。迫切需要能够限制供体风险同时提高移植成功率的生物标志物，以允许安全扩展该领域，这将有助于缓解可用于奥尔特的器官严重短缺的问题。我们计划：1.活体供肝者tnfaip 3基因多态性的研究。2.评估肝移植前肝移植活检组织中A20及其靶基因的表达水平，以及前瞻性患者队列中，再灌注后（受体）或手术结束前（供体）。作为这一目标的一部分，我们还将使用来自供体的外周血单核细胞测定A20 mRNA和蛋白水平。3.在移植物再灌注（受体）或肝切除（供体）之前和之后，测量受体和供体血清中引发细胞因子（TNF和IL-6）的循环水平。4.将tnfaip 3基因多态性、A20表达水平及其靶基因的表达水平与引发细胞因子的循环水平和再生状态相关联，如通过动态对比增强多探测器CT确定的（DCE-MDCT），随后进行定性和定量3D分析和MeVis重建，肝功能（肝酶和凝血试验）和早期临床结果（出院时间、原发性功能障碍、是否需要再次移植）。这项工作中收集的数据将促进使用A20基因多态性和表达水平作为可靠的选择标记，用于LDLT中供体和受体的配对，以降低供体发病率并改善受体结果。 公共卫生相关性：原位肝移植（奥尔特）是急性或慢性肝功能衰竭患者的一种挽救生命的措施。然而，需求大大超过器官供应，导致一些病人在等待名单上死亡。活体肝移植（LDLT）已成为缓解可用于奥尔特的器官短缺的解决方案。然而，在成人中，LDLT受到可以安全收获的移植物大小的限制。由tnfaip 3/A20基因多态性确定的肝保护蛋白A20的表达水平和功能是有前途的工具，可用作LDLT中配对供体和受体的选择生物标志物，这将降低供体发病率并改善受体结局。A20作为LDLT中可靠的预后生物标志物的验证可以作为供体充足性的客观衡量标准，并有助于扩大LDLT，劈肝和奥尔特的领域。