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对影响活体供体肝切除术后或活体供体肝移植（LDLT）中接受部分肝同种异体移植后肝组织再生能力的因素进行深入检查。在动物模型中，A20基因复合物已被证明参与致死性肝切除术后的肝再生，在人类中，A20的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。这些研究将确定A20多态性和供体肝脏中的表达水平是否可以作为成功LDLT的可靠预后标志物。将进行以下研究：1）将使用供体外周血细胞，使用单核苷酸多态性探测LDLT供体中的A20多态性; 2）将在移植时和临床情况需要时获得灌注前和灌注后肝活检。A20 mRNA采用定量PCR检测，A20 mRNA的细胞分布采用免疫组化检测，A20 mRNA的细胞分布采用免疫组化检测，A20 mRNA的细胞因子和生长因子的水平采用免疫组化检测; 3）在移植/捐献后第1、3、5、7天以及再次入院时，检测LDLT供受者的生物学和分子标志物; 4）数据将与临床过程和肝再生相关，如通过体积CT检查的MeVis重建所确定的。第二个目的是研究门静脉高压症在肝移植后小肝综合征发生中的作用。将通过直接测量门静脉压力来确定发病率，并将研究降低压力的程序。将分析结局，包括小体积综合征的发生、肝再生和不良结局，包括死亡和再次移植的需要。通过比较经验证的生活质量仪器的结果与捐赠后1年、2年和5年肝再生的CT体积测定，检查肝再生对LDLT供体的影响。最后，将研究供体和受体社会经济因素对获得LDLT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，并有可能确定用于预防或治疗肝移植功能障碍的基于A20的疗法，确定和设计门静脉过度灌注的治疗策略，确定肝再生对供体生活质量的影响，并证明增强或阻碍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.