PROTEIN SYNTHESIS IN NORMAL AND REGENERATING LIVER

正常肝脏和再生肝脏中的蛋白质合成

• 批准号: 6830297
• 负责人: DAVID A SHAFRITZ
• 金额: $ 48.71万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-05-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830297
• 关键词: PROTEIN; SYNTHESIS; NORMAL; REGENERATING; LIVER

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

近年来，人们对鉴定各种组织中的祖细胞或干细胞及其用于组织再生的潜在用途产生了相当大的兴趣。使用一种天然的，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在10分钟内重新增殖，正常肝实质肿块的4%，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性长达六个月（通常归因于干细胞的特性）。我们假设使用正常的基于肝脏的细胞移植系统，例如我们已经建立的系统，在确定分离的细胞和细胞系的干细胞潜能以及有助于其在肝脏中增殖和分化的因素方面是至关重要的。在这一背景下，建议进行以下实验：1）在我们的肝脏细胞移植模型中使用细胞因子和药理学试剂来增加移植的胎肝细胞的增殖，2）研究移植后不同增殖胎肝上皮细胞群体的分子和细胞特征，以确定其表型、增殖潜力、谱系衍生能力和自我更新的能力和3）确定成熟肝细胞是否可以从实质进入胆管室并表现出足够的可塑性以转换其表型并并入胆管，这表明肝小叶中的植入位点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，与大鼠相当，但现在也免疫受损（Rag 2-/-），以允许用选定的转基因和敲除动物进行再增殖研究，这些动物表现出修饰的细胞周期调节、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肝源性细胞来增强肝脏再生的方法，最终将导致人类的临床应用。性能现场=