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PROTEIN SYNTHESIS IN NORMAL AND REGENERATING LIVER

正常肝脏和再生肝脏中的蛋白质合成

基本信息

批准号：
7161773
负责人：
DAVID A SHAFRITZ
金额：
$ 47.54万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/7161773
关键词：
Address Adult Basement membrane Bile Duct Epithelium Bile fluid Biliary Cell Cycle Regulation Cell Line Cell Transplantation Cell Transplants Cells Characteristics Confocal Microscopy Engraftment Environment Epithelial Epithelial Cells Exhibits Fetal Liver Goals Growth Factor Hepatic Hepatocyte Human Immunocompromised Host Immunoelectron Microscopy Immunohistochemistry In Situ Hybridization Individual Interleukin-6 Knockout Mice Laboratories Lead Liver Lobule Methods Modeling Molecular Mus Mutation Natural regeneration Partial Hepatectomy Phenotype Population Procedures Proliferating Property Protein Biosynthesis Rattus Side Site Sodium Deoxycholate Stem cells System Thyroid Hormones Time Tissues Transgenic Mice Transgenic Organisms Transplantation base bile duct bile ductular clinical application cytokine design fetal interest knockout animal laser capture microdissection liver transplantation mouse model mutant oval cell p27 Cell Cycle Protein p27 Enzyme Inhibitor progenitor research study self-renewal stem

项目摘要

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.

近年来，人们对在各种肿瘤中鉴定祖细胞或干细胞产生了相当大的兴趣。组织及其用于组织再生的潜在用途。利用一种天然的独特细胞肝移植系统（DPPIV-突变Fischer 344大鼠），我们实验室的研究已经证明，早期胎肝上皮细胞可以重新填充到10.4的实质，正常肝脏中的肿块，产生肝细胞和胆管上皮细胞后代，并显示在细胞移植后持续增殖活性长达六个月（一般性质干细胞（Stem Cells）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，在确定分离细胞的干细胞潜能方面至关重要以及细胞系和有助于它们在肝脏中增殖和分化的因子。在此背景下，提出了以下实验：1）使用细胞因子和药理学试剂，在我们的基于肝脏的细胞移植模型中增加移植的胎肝细胞的增殖， 2)研究不同人群增殖胎儿的分子和细胞特征，肝上皮细胞移植后，以确定其表型，增殖潜力，谱系获得自我更新的能力和能力，以及3）确定成熟肝细胞是否可以从实质进入胆管腔室，并表现出足够的可塑性，它们的表型，并成为纳入胆管，证明植入位点，肝小叶决定移植肝细胞的最终命运。我们还将使用最近建立了与大鼠相当的DPPIV -/-小鼠模型，但现在也免疫受损（Rag 2-/-），以允许用选择的转基因和敲除动物进行再增殖研究，所述动物表现出改变的细胞周期调节、生长因子增强或细胞因子依赖性增殖。的这些研究的总体目标是找到通过肝移植增强肝脏再生的方法，最终将导致人类临床应用的衍生细胞。