Notch Effects on Hematopoietic Repopulating Cells

Notch 对造血再生细胞的影响

• 批准号: 7145860
• 负责人: IRWIN D BERNSTEIN
• 金额: $ 43.25万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145860
• 关键词: NOD mouse; SCID mouse; cell differentiation; cell population study; cell proliferation; cell surface receptors; clinical research; cord blood; hematopoiesis; hematopoietic stem cells; human tissue; small interfering RNA; stem cell transplantation; transcription factor

DESCRIPTION (provided by applicant): Notch receptors are widely expressed by hematopoietic precursor cells and the differentiation of hematopoietic precursors is inhibited when these cells are induced to overexpress the constitutively active cytoplasmic domain of Notch1 or when they are exposed to exogenously presented Notch ligand forms. Our studies show that culture of human cord blood cells in the presence of engineered Notch ligand leads to increased numbers of CD34+ precursors, including those able to repopulate immunodeficient mice, and our preliminary data indicate that the dose of Notch ligand plays a critical role in determining hematopoietic stem cell fate. Based on these observations, we hypothesize that the use of different doses and types of Notch ligands can serve to enhance the self-renewal of hematopoietic repopulating cells. To further investigate the role of Notch signaling in hematopoiesis and its effect on stem cell proliferation and differentiation, we will determine: dose-dependent effects of the Notch ligand Delta1 on the growth and differentiation of CD34+CD38- cord blood precursors, in particular on the generation of short- and long-term NOD/SCID repopulating cells (Aim 1); whether different Notch ligand types induce Notch signaling that differentially affects the proliferation and differentiation of CD34+CD38- cord blood cells (Aim 2); and whether induction of different cell fates by different doses or types of Notch ligands results from differences in the constellation of induced Notch target genes (Aim 3). Our overall goal is to define the effects of ligand-induced Notch signaling on hematopoietic stem cell proliferation and differentiation as the basis for methods to manipulate this activity for therapeutic application, in particular, for improving umbilical cord blood transplantation.

描述（申请人提供）：Notch 受体由造血前体细胞广泛表达，并且当这些细胞被诱导过度表达 Notch1 的组成型活性细胞质结构域或当它们暴露于外源性存在的 Notch 配体形式时，造血前体细胞的分化受到抑制。 我们的研究表明，在工程化Notch配体存在的情况下培养人脐带血细胞会导致CD34+前体数量增加，包括那些能够在免疫缺陷小鼠中重新繁殖的前体，并且我们的初步数据表明Notch配体的剂量在决定CD34+前体的数量方面发挥着关键作用。造血干细胞的命运。 基于这些观察，我们假设使用不同剂量和类型的Notch配体可以增强造血再生细胞的自我更新。 为了进一步研究Notch信号在造血中的作用及其对干细胞增殖和分化的影响，我们将确定：Notch配体Delta1对CD34+CD38-脐带血前体细胞生长和分化的剂量依赖性影响，特别是对短期和长期 NOD/SCID 再生细胞的产生（目标 1）；不同的Notch配体类型是否会诱导Notch信号传导，从而对CD34+CD38-脐带血细胞的增殖和分化产生不同的影响（目标2）；不同剂量或类型的 Notch 配体诱导不同的细胞命运是否是由于诱导的 Notch 靶基因群的差异所致（目标 3）。 我们的总体目标是确定配体诱导的 Notch 信号传导对造血干细胞增殖和分化的影响，作为操纵这种活性进行治疗应用的方法的基础，特别是改善脐带血移植。