EphB4 modulates hemangioblast development

EphB4 调节成血管细胞发育

• 批准号: 7156059
• 负责人: ZACK Z. WANG
• 金额: $ 6.83万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-10 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156059
• 关键词: CD34 molecule; angiogenesis; biological signal transduction; bone marrow transplantation; cell differentiation; cell proliferation; cell surface receptors; ephrins; erythroid stem cell; flow cytometry; genetically modified animals; hematopoiesis; hematopoietic stem cells; laboratory mouse; ligands; polymerase chain reaction; vascular endothelium

DESCRIPTION (provided by applicant): Stem cells have the capacity to self-renew and to generate differentiated cells. Both adult and embryonic stem cells hold great potential for regenerative medicine, and gene therapy. Hematopoietic stem cells (HSCs) have been the most extensively studied and serve as a prototype model to define the general biological properties of stem cells. During embryogenesis, hematopoiesis is highly coordinated with angiogenesis. Recent studies have suggested that hematopoietic and endothelial precursors originate from a common ancestor, the hemangioblast. The key molecular players determining the fate of the hemangioblast are not fully elucidated. Receptor tyrosine kinases (RTKs), receiving and interpreting extracellular signals, play an important role in cell proliferation and differentiation. Endothelial cell receptor tyrosine kinase EphB4 (HTK) and its ligand, ephrinB2, are critical for angiogenesis. Loss of either EphB4 or ephrinB2 cause fatal abnormalities of capillary formation in null mice. We originally identified EphB4 from human bone marrow CD34+ cells. Our recent studies indicated that forced expression of EphB4 influence the function and phenotype of primitive human hematopoietic cells, enforcing preferential megakaryocytic and erythroid differentiation. This proposal seeks to further assess the role of EphB4 signaling in hematopoietic stem cells and the possibility that the EphB4 may be a common molecule bridging angiogenesis and hematopoiesis. In vitro assays of embryonic stem (ES) cells and in vivo experiments, including knockout mice and bone marrow transplantation, will be conducted to assess the differentiation potential of either genetically deficient or activated EphB4. Our preliminary data from in vitro differentiation of genetically engineered ES cells show that EphB4 signaling plays an important role in hemangioblasts and the early development of hematopoietic and endothelial cells. These studies identify EphB4 as one of the molecular modulators of hemangioblast formation. If successful, the results of this proposal will provide insight into the molecular mechanisms governing hemangioblasts and their differentiation along vascular and hematopoietic lineages. Manipulation of the signals that control hematopoiesis and vasculogenesis offer a broad spectrum of therapeutic potential for hematologic, oncologic and cardiovascular diseases. This Mentored Research Scientist Development Award will substantially advance the candidate's goal of developing an independent basic research program in an academic institution while contributing new training in stem cell biology and angiogenesis.

描述（由申请人提供）： 干细胞具有自我更新和产生分化细胞的能力。成体干细胞和胚胎干细胞在再生医学和基因治疗方面都具有巨大的潜力。造血干细胞（HSC）得到了最广泛的研究，并作为定义干细胞一般生物学特性的原型模型。在胚胎发生过程中，造血与血管生成高度协调。最近的研究表明，造血和内皮前体细胞起源于一个共同的祖先，即成血管细胞。决定成血管细胞命运的关键分子尚未完全阐明。受体酪氨酸激酶（RTK）接收和解释细胞外信号，在细胞增殖和分化中发挥重要作用。内皮细胞受体酪氨酸激酶 EphB4 (HTK) 及其配体 ephrinB2 对于血管生成至关重要。 EphB4 或 ephrinB2 的缺失会导致无效小鼠毛细血管形成的致命异常。我们最初从人骨髓 CD34+ 细胞中鉴定出 EphB4。我们最近的研究表明，EphB4 的强制表达会影响原始人类造血细胞的功能和表型，强制巨核细胞和红系细胞优先分化。该提案旨在进一步评估 EphB4 信号传导在造血干细胞中的作用以及 EphB4 可能是桥接血管生成和造血的常见分子的可能性。将进行胚胎干 (ES) 细胞的体外测定和体内实验，包括基因敲除小鼠和骨髓移植，以评估遗传缺陷或激活的 EphB4 的分化潜力。我们对基因工程 ES 细胞体外分化的初步数据表明，EphB4 信号在成血管细胞以及造血细胞和内皮细胞的早期发育中发挥着重要作用。这些研究将 EphB4 确定为成血管细胞形成的分子调节剂之一。如果成功，该提案的结果将提供对控制成血成血管细胞及其沿血管和造血谱系分化的分子机制的深入了解。控制造血和血管发生的信号的操纵为血液学、肿瘤学和心血管疾病提供了广泛的治疗潜力。 该导师研究科学家发展奖将极大地推进候选人在学术机构中开发独立基础研究项目的目标，同时为干细胞生物学和血管生成方面的新培训做出贡献。