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）：我们的长期工作表明A20（TNFAIP3）增强了肝脏对损伤的抗炎，抗凋亡和抗氧化剂反应，并促进肝细胞增殖和肝脏再生。在实验动物模型中，我们已经表明，在肝脏根本致命的肝切除术和严重的肝缺血再灌注损伤后，肝脏中A20的过表达具有保护性，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在支持肝脏再生中的重要生理作用。确实，我们表明，在杂合子小鼠中看到的部分A20敲低（A20）显着损害了肝脏再生，并在2/3部分肝切除术后增加致死性。最近，在人类全基因组关联研究中，TNFAIP3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基因座。在该提案中，我们希望确定A20基因多态性以及A20及其靶基因在移植物中是否可以用作可靠的预后标记，用于肝脏再生和活物供体肝移植（LDLT）中的肝脏再生和功能。 LDLT已成为一种解决方案，以缓解可用于原位肝移植（OLT）的器官短缺。但是，它在成年人中的广泛使用受到可以安全收获的移植物的大小的限制。需要在改善移植成功的同时限制捐助者的风险的生物标志物，以确保对该领域的安全扩张，这将有助于缓解可用于OLT的器官的严重短缺。我们计划：1。探测所有活肝供体中TNFAIP3基因多态性的探测。 2。评估肝移植前的肝移植活检中A20及其靶基因的表达水平，在再灌注后（接受者）或手术结束前（供体）（供体），在患者的前瞻性队列中评估A20的表达水平。作为此目标的一部分，我们还将使用供体的外周血单核细胞来确定A20 mRNA和蛋白质水平。 3.在接枝再灌注（受体）或肝切除术（供体）之前和之后，测量受体和供体血清中启动细胞因子（TNF和IL-6）的循环水平。 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早期的临床结果（排放的时间，主要功能障碍，重新进行需要）。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配对供体和LDLT中的接受者的可靠选择标记，以降低供体的发病率并改善受体结果。 公共卫生相关性：原位肝移植（OLT）是患有急性或慢性肝衰竭患者的挽救生命措施。但是，需求大大超过了器官的可用性，导致许多患者在候补名单上死亡。活着的供体肝移植（LDLT）已成为一种解决方案，以缓解可用于OLT的器官的短缺。但是，在成年人中，LDLT受到可以安全收获的移植物的大小的限制。由TNFAIP3/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希望的工具，可以用作LDLT中配对供体和受体的选择生物标志物，这将降低供体的发病率并改善受体的影响。在LDLT中，A20作为可靠的预后生物标志物的验证可以作为对供体充分性的客观度量，并可以帮助扩大LDLT，Split肝脏和OLT的领域。