BOEC in Biology

BOEC 生物学

• 批准号: 6746013
• 负责人: ROBERT P HEBBEL
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746013
• 关键词: NOD mouse; SCID mouse; apoptosis; bone marrow; cell biology; clinical research; coagulation factor VIII; gene expression; gene therapy; hematopoietic stem cells; hematopoietic tissue transplantation; histamine; histogenesis; human tissue; integrins; interleukin 6; intravenous administration; monoclonal antibody; polymerase chain reaction; selectins; spleen; stem cell transplantation; tissue /cell culture; transfection /expression vector; vascular cell adhesion molecule; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Our preliminary data indicate that molecularly engineered BOEC (blood outgrowth endothelial cells) can be used for effective gene therapy of hemophilia A. The present project will examine several aspects of BOEC biology that are directly relevant to this potential therapeutic use of BOEC. Three Specific Aims will utilize the model of human BOEC (either unmanipulated or engineered to express human factor VIII) given to NOD. SCID mice. In Aim 1 we will identify the marrow "homing" behavior of BOEC. We will determine where BOEC go in the short- and long-terms when given intravenously. We will identify mechanisms underlying BOEC seeding of marrow and spleen. We will determine if BOEC seeding of marrow/spleen can be increase pharmacologically (with histamine, or beta-1-integrin activating antibody, or VEGF, or 1L6 plus stem cell factor). We will determine if the apparently low seeding frequency of BOEC in marrow is a stochastic or pre-programmed characteristic of establishing a BOEC graft. In Aim 2 we will examine certain issues regarding BOEC graft expansion and longevity in vivo. We will confirm our preliminary impression that BOEC expand substantially in vivo after being administered intravenously. We will determine if this in vivo expansion is predicatble and is dependent on the prior passaging history of the BOEC. We will seek to confirm that silencing of our fVIlI transgene expression vector is not a problem in BOEC. in Aim 3 we expect to document that endothelial expansion in vivo after intravenous administration of BOEC is due to a true BOEC cell rather than a contaminating hematopoietic precursor cell. Each of these studies addresses an issue that is necessary to understand before BOEC technology can be applied for therapeutics. Aside from eventual therapeutics, these studies will define aspects of this unique cell type.

描述（由申请人提供）：我们的初步数据表明，分子工程BOEC（血液生长内皮细胞）可用于血友病A的有效基因治疗。本项目将研究BOEC生物学的几个方面，这些方面与BOEC的潜在治疗用途直接相关。Three Specific Aims将利用给予NOD的人BOEC模型（未经操作或经工程改造以表达人因子VIII）。SCID小鼠。在目标1中，我们将确定骨髓“归巢”行为的BOEC。我们将确定BOEC在短期和长期静脉注射时的去向。我们将确定骨髓和脾脏的BOEC接种的机制。我们将确定骨髓/脾脏的BOEC接种是否可以增加（用组胺或β-1-整联蛋白激活抗体或VEGF或1 L 6加干细胞因子）。我们将确定骨髓中BOEC的明显低接种频率是否是建立BOEC移植物的随机或预编程特征。在目标2中，我们将研究有关BOEC移植物扩张和体内寿命的某些问题。我们将证实我们的初步印象，即BOEC在静脉内给药后在体内大量扩增。我们将确定这种体内扩增是否是可预测的，是否取决于BOEC先前的传代历史。我们将寻求证实我们的fVII I转基因表达载体的沉默在BOEC中不是问题。在目的3中，我们期望证明静脉内施用BOEC后体内内皮扩增是由于真正的BOEC细胞而不是污染的造血前体细胞。这些研究中的每一项都解决了在BOEC技术应用于治疗之前需要了解的问题。除了最终的治疗方法，这些研究将定义这种独特细胞类型的各个方面。