PROTEIN SYNTHESIS IN NORMAL AND REGENERATING LIVER

近年来，人们对鉴定各种组织中的祖细胞或干细胞及其在组织再生中的潜在用途产生了相当大的兴趣。利用一种天然存在的、独特的肝脏细胞移植系统（DPPIV-突变的Fischer 344大鼠），我们实验室的研究表明，早期胎儿肝上皮细胞可以重新填充正常肝脏实质团块的10.4%，产生肝细胞和胆管上皮细胞后代，并在细胞移植后长达6个月的时间里显示出持续的增殖活性（通常归因于干细胞的特性）。我们假设使用正常的肝细胞移植系统，例如我们已经建立的系统，对于确定分离细胞和细胞系的干细胞潜力以及促进其在肝脏中增殖和分化的因素至关重要。在此背景下，建议进行实验：1)利用细胞因子和药物增强移植胎儿肝细胞的增殖，建立基于肝脏的细胞移植模型；2)研究移植后不同群体增殖胎儿肝上皮细胞的分子和细胞特征，明确其表型、增殖潜力；谱系衍生能力和自我更新能力；3)确定成熟肝细胞是否能从实质进入胆管室，并表现出足够的可塑性，以改变其表型并融入胆管，这表明肝小泡的植入部位决定了移植肝细胞的最终命运。我们还将使用最近建立的与大鼠相当的DPPIV -/-小鼠模型，但现在也免疫功能低下（Rag2-/-），允许选择转基因和敲除动物进行再种群研究，这些动物表现出修改的细胞周期调节，生长因子增强或细胞因子依赖性增殖。这些研究的总体目标是找到通过移植的肝源性细胞来增强肝脏再生的方法，并最终用于人类的临床应用。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED, In recent years, there has been considerable interest in identifying progenitor or stem cells in various tissues and their potential use for tissue repopulation. Using a naturally occurring, unique cell transplantation system for the liver (the DPPIV- mutant Fischer 344 rat), studies in our laboratory have demonstrated that early fetal liver epithelial cells can repopulate up to 10¿,4 of the parenchymal mass in normal liver, produce both hepatocytic and bile duct epithelial cell progeny and show continued proliferative activity for up to six months after cell transplantation (properties generally attributed to stem cells). We hypothesize that use of a normal liver-based cell transplantation system, such as the one we have established, is critical in determining the stem cell potential of isolated cells and cell lines and the factors that contribute to their proliferation and differentiation in the liver. Within this context, experiments are proposed: 1) to use cytokines and pharmacological agents to augment proliferation of transplanted fetal hepatic cells in our liver-based cell transplantation model, 2) to study the molecular and cellular characteristics of different populations of proliferating fetal liver epithelial cells after transplantation to define their phenotype, proliferative potential, lineage deriving capacity and ability for self renewal and 3) to determine whether mature hepatocytes can pass from the parenchyma into the biliary compartment and exhibit sufficient plasticity to switch their phenotype and become incorporated into bile ducts, demonstrating that the engraftment site in the liver iobule determines the ultimate fate of transplanted hepatic cells. We will also use a recently established DPPIV -/- mouse model comparable to the rat, but now also immunocompromised (Rag2-/-), to permit repopulation studies with selected transgenic and knockout animals exhibiting modified cell cycle regulation, growth factor enhanced or cytokine dependent proliferation. The overall goal of these studies is to find methods to enhance liver repopulation by transplanted hepatic derived cells that will ultimately lead to clinical application in humans. PERFORMANCE SITE ========================================Section End===========================================