LDLT: Diagnostic Markers of Liver Regeneration to Predict Outcomes

描述(由申请人提供)：本提案的主要部分涉及深入研究影响活体供肝切除或在活体供肝移植(LDLT)中接受部分同种异体肝移植后肝组织再生能力的因素。在动物模型中，A20基因复合体已被证明参与了致死性肝切除后的肝再生，而在人类中，A20基因的多态性已被确定为几种炎症性和自身免疫性疾病的易感基因。这些研究将确定供体肝脏中A20基因的多态性和表达水平是否可以作为LDLT成功的可靠预后标志。将进行以下研究：1)利用供者外周血细胞检测供者的A20基因多态性；2)在移植时和临床需要时进行肝脏灌流前和灌流后的活检。通过定量聚合酶链式反应检测A20mRNA，免疫组织化学方法检测A20mRNA的细胞分布，检测启动细胞因子和生长因子水平；3)在供受者移植/捐献后第1、3、5、7天和再次入院时检测生物学和分子标志物；4)通过MEVIS重建容积CT检查确定临床病程和肝再生情况。第二个目的是研究门静脉高压症在LDLT术后小体综合征发生中的作用。发病率将通过直接测量门静脉压力来确定，并将调查降低压力的程序。将分析结果，包括小体积综合征的发展，肝脏再生，以及包括死亡和需要再次移植的不良结果。肝再生对LDLT供者的影响将通过比较供者术后1年、2年和5年的生活质量检测结果和CT肝脏再生的体积测定结果来检验。最后，将研究捐赠者和受赠者的社会经济因素对获得最低限度移植的影响。 公共卫生相关性：这些研究将整合临床医生、基础科学家和临床研究人员的专业知识，并有可能确定有助于预防或治疗移植肝功能障碍的A20疗法，确定和设计门静脉高灌流的治疗策略，确定肝再生对供者生活质量的影响，并展示促进或阻碍获得LDLT的社会经济因素。

DESCRIPTION (provided by applicant): The major portion of this proposal involves the in-depth examination of factors that affect the ability of liver tissue to regenerate after live donor hepatectomy or receipt of a partial liver allograft in a living donor liver transplant (LDLT). In animal models, the A20 gene complex has been shown to be involved in hepatic regeneration after lethal hepatectomy, and in humans, polymorphism in A20 have been identified as susceptibility loci for several inflammatory and autoimmune diseases. These studies will determine if A20 polymorphism and level of expression in donor liver may serve as reliable prognostic markers for successful LDLT. The following studies will be performed: 1) A20 polymorphisms in LDLT donors will be probed for using single nucleotide polymorphisms using donor peripheral blood cells; 2) Pre- and post-perfusion liver biopsies will be obtained at the time of transplant and whenever required by clinical situation. A20 mRNA will be determined by quantitative PCR, its cellular distribution will be determined by immunohistochemistry, and levels of priming cytokines and growth factors will be measured; 3) Biological and molecular markers will be examined in LDLT donor and recipients on days 1, 3, 5, and 7 post-transplantation/donation and whenever readmitted to hospital; 4) Data will be correlated with clinical course and hepatic regeneration as determined by MeVis reconstruction of volumetric CT examination. The second aim will investigate the role of portal hypertension in the development of small for size syndrome after LDLT. The incidence will be determined by direct measurement of portal pressure and procedures to reduce pressures will be investigated. Outcomes including development of small for size syndrome, hepatic regeneration, and adverse outcomes including death and need for re-transplantation will be analyzed. The effect of hepatic regeneration on LDLT donors will be examined by comparing results of validated quality of life instruments with CT volumetric determinations of hepatic regeneration at 1, 2, and 5 years after donation. Finally the effect of donor and recipient socioeconomic factors on access to LDLT will be studied. PUBLIC HEALTH RELEVANCE: These studies will integrate the expertise of clinicians, basic scientists, and clinical researchers and have potential to identify A20 based therapies useful for the prevention or treatment of liver graft dysfunction, identify and devise treatment strategies for portal hyperperfusion, identify effect of hepatic regeneration on donor quality of life, and demonstrate socioeconomic factors that enhance or impede access to LDLT.