Biology and function of SALL4-induced hematopoietic stem cells from cord blood

SALL4诱导的脐带血造血干细胞的生物学和功能

• 批准号: 8225815
• 负责人: Jerell Roland Aguila
• 金额: $ 13.07万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225815
• 关键词: Amino Acids; Area; Biological Assay; Biology; Bone Marrow Transplantation; CD34 gene; Cell Therapy; Cell physiology; Cells; Clinical; Communities; Critiques; Disease; Dose; Employee Strikes; Engraftment; Goals; Growth Factor; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic stem cells; Human; In Vitro; Individual; Kinetics; Light; Marrow; Mass Spectrum Analysis; Modeling; N-terminal; Output; Proteins; Recovery; Research; Safety; Stem cells; Subfamily lentivirinae; Technology; Testing; Translating; Umbilical Cord Blood; Umbilical cord structure; Writing; cell growth; cellular transduction; clinical application; cytokine; gene therapy; in vivo; innovation; meetings; overexpression; self-renewal; success

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The expansion of HSCs has remained an important goal to develop advanced cell therapies for bone marrow transplantation and many blood disorders. During the last two to three decades, in which the first hematopoietic growth factors were identified, there have been numerous attempts to expand HSCs in vitro using purified growth factors that are known to regulate HSCs. However, these attempts have been met with limited success for clinical applications. An innovative approach is urgently needed for the research community to succeed in unraveling HSC expansion biology and creating a breakthrough in the ability to expand HSCs in vitro to clinically useful numbers. This would have tremendous impact in the areas of bone marrow transplantation and gene therapy for hematologic cancers and disorders. Toward this end, we have made several striking discoveries that shed new light on HSC expansion using cytokine-dependent SALL4 technology and lay the groundwork for the studies proposed here. We hope our studies will uncover an entirely new form of HSC expansion that could be developed and it is thus feasible to translate this study into the clinical setting. The Specific Aims of our proposal are focused on achieving this objective. Aim 1. To define the kinetics, duration, and magnitude of SALL4-induced enhancement of HSC expansion ex vivo and in vivo. Aim 2-To compare two different approaches to expand human umbilical cord (hUBC) stem cells and characterize the extent of their contribution of short-term and long-term repopulation to marrow recovery. Aim 3. - To identify proteins that specifically interact with the N-terminal domains of SALL4 by taking advantage of protein mass spectrometry from HSCs. PUBLIC HEALTH RELEVANCE: Hematopoietic stem cells (HSCs) are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The expansion of HSCs has remained an important goal to develop advanced cell therapies for bone marrow transplantation and many blood disorders. This would have tremendous impact in the areas of bone marrow transplantation and gene therapy for hematologic cancers and disorders. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.

描述（由申请人提供）：造血干细胞（HSC）是一种罕见的细胞，具有独特的自我更新和分化为所有造血谱系细胞的能力。造血干细胞的扩增一直是开发骨髓移植和许多血液疾病的先进细胞疗法的重要目标。在鉴定出第一批造血生长因子的过去二十至三十年中，已经有许多尝试使用已知调节HSC的纯化的生长因子体外扩增HSC。然而，这些尝试在临床应用中取得了有限的成功。研究界迫切需要一种创新方法来成功解开HSC扩增生物学，并在体外将HSC扩增至临床有用数量的能力方面取得突破。这将在骨髓移植和血液癌症和疾病的基因治疗领域产生巨大影响。为此，我们已经取得了几项惊人的发现，这些发现为使用依赖于精氨酸的SALL 4技术进行HSC扩增提供了新的线索，并为本文提出的研究奠定了基础。我们希望我们的研究将揭示一种全新的HSC扩增形式，从而将这项研究转化为临床环境是可行的。我们的提案的具体目标就是要实现这一目标。目标1.确定SALL 4诱导的HSC体外和体内扩增增强的动力学、持续时间和幅度。目的2-比较两种不同的方法来扩大人脐带（hUBC）干细胞和表征其短期和长期再增殖骨髓恢复的贡献程度。目标3. - 利用蛋白质质谱技术从HSC中鉴定与SALL 4 N端结构域特异性相互作用的蛋白质。 公共卫生相关性：造血干细胞（HSCs）是一种罕见的细胞，具有独特的自我更新和分化为所有造血谱系细胞的能力。造血干细胞的扩增一直是开发骨髓移植和许多血液疾病的先进细胞疗法的重要目标。这将在骨髓移植和血液癌症和疾病的基因治疗领域产生巨大影响。 个别评审员的书面评论和标准评分在下面的“评论”部分以基本上未经编辑的形式提供。请注意，这些评论和标准评分是在会议之前准备的，在审查会议上进行任何讨论之后可能没有进行修订。上文“讨论的简历和摘要”部分总结了委员会的最终意见。