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Transplantation of Endothelial Cells

内皮细胞移植

基本信息

批准号：
8012059
负责人：
SANJEEV GUPTA
金额：
$ 10万
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：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8012059
关键词：
A Mouse Address Anatomy Animal Model Animals Area Behavior Biological Biological Models Blood Coagulation Factor Cell Communication Cell Differentiation Induction Cell Survival Cell Therapy Cell Transplantation Cell Transplants Cells Cellular biology Development Discontinuous Capillary Disease Endothelial Cells Engraftment Factor VIII Genes Genetic Goals Hemophilia A Hepatic Hepatic Mass Hepatocyte Hepatocyte Growth Factor Human Immune response Immunodeficient Mouse Knockout Mice Lentivirus Vector Liver Liver Regeneration Modeling Modification Mus Natural History Paracrine Communication Physiological Population Process Proliferating Property Reporter Genes Research Personnel Stem cells Stimulus System Testing Therapeutic Transgenes Transplantation Treatment Efficacy Vascular Endothelial Growth Factors Viral Vector Work base cell type clinical application gene therapy genetic manipulation human disease human stem cells improved in vivo insight intercellular communication liver transplantation mouse model novel precursor cell programs response stem stem cell biology therapeutic gene

项目摘要

Liver-directed cell therapy has siginificant potential for many disorders. Studies of hepatocyte transplantation provided insights into cell therapy, as well as novel models for basic studies concerning liver regeneration and stem cell biology. We now wish to define the potential of additional liver cell types, especially endothelial cells, which constitute a major liver cell compartment and contribute in cell-cell signaling, coagulation factor synthesis and immunological responses. Our major hypothesis is that sinusoidal liver endothelial cells will engraft and proliferate in the liver of suitable recipients. Insights into these properties of liver endothelial cells will offer ways to treat specific disorders and to modulate the behavior of other liver cell types for various applications. Therefore, we propose to conduct studies in mice for establishing mechanisms concerning the survival, fate and function of transplanted endothelial cells. Our specific objectives are to first establish the efficiency with which transgenically marked endothelial cells will engraft in the liver of congeneic recipients, including after the introduction of reporter genes with viral vectors, and demonstrate specific mechanisms that would facilitate engraftment and/or proliferation of transplanted endothelial cells. We will then examine whether therapeutic genes can be successfully expressed in transplanted endothelial cells and whether the natural history of hepatic disease processes could be altered by such manipulations. Furthermore, we will examine whether cell-cell interactions can be reproduced in the in vivo setting, such that engraftment of transplanted mouse or human hepatocytes could be modulated in immunodeficient animals by cotransplantation of endothelial cells. Also, we will examine whether transplantation of unperturbed or genetically modified endothelial liver cells and transplantation of endothelial stem/progenitor cells could help ameliorate disease in mice. We expect that these studies will generate insights into endothelial cell biology, offer novel biological models and help define the therapeutic potential of liver endothelial cells.

肝脏定向细胞疗法对许多疾病具有显著的潜力。肝细胞移植的研究为细胞治疗提供了新的见解，也为有关肝再生的基础研究提供了新的模型。和干细胞生物学我们现在希望确定其他肝细胞类型的潜力，特别是内皮细胞。细胞，其构成主要的肝细胞区室并在细胞-细胞信号传导中起作用，凝血因子合成和免疫反应。我们的主要假设是肝窦内皮细胞在合适的受体的肝脏中移植和增殖。深入了解肝内皮细胞的这些特性将提供治疗特定疾病的方法，并调节其他肝细胞类型的行为，应用.因此，我们建议在小鼠中进行研究，以建立有关移植内皮细胞的存活、命运和功能。我们的具体目标是首先建立转基因标记的内皮细胞移植入同种受体肝脏的效率，包括用病毒载体引入报告基因后，并证明了特定的机制这将促进移植的内皮细胞的植入和/或增殖。然后我们将检查治疗基因是否能在移植的内皮细胞中成功表达，肝病过程的自然史可以通过这种操作改变。此外，我们将检查细胞-细胞相互作用是否可以在体内环境中再现，使得移植的小鼠或人肝细胞可以通过以下方式在免疫缺陷动物中调节：内皮细胞共移植。此外，我们将研究是否移植的无干扰或基因修饰的内皮肝细胞和内皮干/祖细胞移植可以帮助改善小鼠的疾病。我们希望这些研究将产生对内皮细胞生物学的见解，提供了新的生物学模型，并有助于确定肝内皮细胞的治疗潜力。