Hematopoietic Stem Cell Gene Transfer

造血干细胞基因转移

• 批准号: 6656059
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 39.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-05 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6656059
• 关键词: AIDS therapy; CD34 molecule; HIV infections; NOD mouse; SCID mouse; T lymphocyte; cell proliferation; clinical research; gene delivery system; gene expression; gene therapy; hematopoietic stem cells; human immunodeficiency virus 1; human subject; polymerase chain reaction; transfection /expression vector; xenotransplantation

DESCRIPTION (provided by the applicant): Hematopoietic stem cells (HSC) play a central role in the production of all hematopoietic lineages. HSC are functionally defined as having two important characteristics: self-renewal and the capacity to differentiate into all mature hematopoietic lineages. These two characteristics are in sharp contrast to those of mature cells that have limited proliferation and differentiation potential and lack self-renewal properties. In order to maintain a functional hematopoietic system, a population of HSC must be able to regenerate the entire hematopoietic repertoire on a regular basis. Whereas HSC are readily evaluated by transplantation in mice, analysis in humans is quite difficult. Progress in the characterization of HSC has relied, for the most part, on in vitro assays such clonogenic assays (CFCs) and of long-term cultures (LTC-IC). Interest in HSC is widespread because of their many possible clinical applications including transplantation, purging of tumor cells, and gene therapy. Recently, the use of xenografts has facilitated the analysis of the HSC. These models are based on the fact that human hematopoietic cells from fetal liver, bone marrow, umbilical core or peripheral blood (after mobilization) can repopulate the bone marrow of severe combined immune deficient (SCID) mice. In this competitive renewal application in which the investigators propose to use two different but complementary xenograft models to evaluate the in vivo repopulating potential and the suitability for gene transfer of HSC from HIV infected individuals. Since ultimately this is the only source available for cells of future gene therapy protocols. The specific aims of this proposal are: 1) To determine the quantitative in vivo repopulating potential of hematopoietic stem cells from HIV-1 infected individuals; 2) To determine the in vivo lymphopoietic capacity of T-cell progenitors from HIV-1 individuals; and 3) To characterize the primitive hematopoietic stem cell compartment in HIV-1 infected individuals.

描述（由申请人提供）：造血干细胞（HSC）在所有造血谱系的产生中发挥着核心作用。 HSC在功能上被定义为具有两个重要特征：自我更新和分化为所有成熟造血谱系的能力。 这两个特征与具有有限增殖和分化潜力并且缺乏自我更新特性的成熟细胞形成鲜明对比。 为了维持功能性造血系统，HSC群体必须能够定期再生整个造血库。 尽管HSC容易通过小鼠移植进行评估，但在人类中进行分析是相当困难的。 HSC的表征进展在很大程度上依赖于体外试验，如克隆形成试验（CFC）和长期培养试验（LTC-IC）。 由于HSC具有许多可能的临床应用，包括移植、清除肿瘤细胞和基因治疗，因此对HSC的兴趣是广泛的。 最近，异种移植物的使用促进了HSC的分析。 这些模型基于以下事实：来自胎肝、骨髓、脐带芯或外周血（动员后）的人造血细胞可以重新填充严重联合免疫缺陷（SCID）小鼠的骨髓。在这项竞争性更新申请中，研究人员建议使用两种不同但互补的异种移植模型来评估体内再生潜力和从HIV感染个体转移HSC基因的适用性。 因为最终这是未来基因治疗方案的细胞的唯一来源。 该建议的具体目的是：1）确定来自HIV-1感染个体的造血干细胞的定量体内再增殖潜力; 2）确定来自HIV-1个体的T细胞祖细胞的体内淋巴细胞生成能力;和3）表征HIV-1感染个体中的原始造血干细胞区室。