PROTEIN SYNTHESIS IN NORMAL AND REGENERATING LIVER

由于超出了所提供的空间，近年来，人们对识别各种组织中的祖细胞或干细胞及其用于组织再繁殖的潜在用途非常感兴趣。使用一种自然产生的独特的肝脏细胞移植系统(DPPIV突变体Fischer 344大鼠)，我们实验室的研究表明，早期胎肝上皮细胞可以在正常肝脏中重新填充多达10？4的实质块，产生肝细胞和胆管上皮细胞后代，并在细胞移植后显示持续增殖活动长达六个月(通常被认为是干细胞的特性)。我们假设，使用正常的基于肝脏的细胞移植系统，如我们已经建立的系统，对于确定分离的细胞和细胞系的干细胞潜力以及有助于它们在肝脏中增殖和分化的因素至关重要。在此背景下，我们建议进行以下实验：1)在我们的肝细胞移植模型中，使用细胞因子和药物促进移植的胎肝细胞的增殖；2)研究移植后不同群体增殖的胎肝细胞的分子和细胞特性，以确定其表型、增殖潜能、谱系分化能力和自我更新能力；3)确定成熟肝细胞是否能够从实质进入胆管并显示足够的可塑性来改变其表型并整合到胆管中，表明肝小叶内的植入位置决定了移植肝细胞的最终命运。我们还将使用最近建立的DPPIV-/-小鼠模型，与大鼠类似，但现在也是免疫受损的(Rag2-/-)，以允许对选定的转基因和敲除动物进行再繁殖研究，这些动物表现出细胞周期调节改变、生长因子增强或细胞因子依赖的增殖。这些研究的总体目标是找到通过移植肝来源细胞来促进肝脏再繁殖的方法，最终将导致临床应用。表演网站========================================Section End===========================================

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===========================================