LDLT: Diagnostic Markers of Liver Regeneration to Predict Outcomes

描述（由申请人提供）：该提案的主要部分涉及对活体供肝切除术或活体供肝移植（LDLT）中接受部分同种异体肝脏移植后影响肝组织再生能力的因素的深入研究。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脏再生，在人类中，A20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。这些研究将确定供体肝脏中A20多态性和表达水平是否可以作为LDLT成功的可靠预后指标。将进行以下研究：1)利用供者外周血的单核苷酸多态性来探测LDLT供者的A20多态性；2)移植时及临床需要时，进行肝灌注前及灌注后活检。定量PCR检测A20 mRNA，免疫组化检测其细胞分布，检测启动细胞因子和生长因子水平；3)在移植/捐献后1、3、5和7天以及再次入院时，检查LDLT供体和受体的生物学和分子标志物；4)数据将与临床病程和肝脏再生相关，由体积CT检查的MeVis重建确定。第二个目的是研究门脉高压在LDLT后小尺寸综合征发展中的作用。发生率将通过直接测量门静脉压力来确定，并将研究减压的方法。结果包括小尺寸综合征的发展、肝脏再生、不良结果包括死亡和需要再次移植。肝再生对LDLT供者的影响将通过将捐献后1年、2年和5年经验证的生活质量仪器的结果与CT体积测定的肝再生结果进行比较来检验。最后，研究供体和受体社会经济因素对LDLT获取的影响。

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.