BAALC in neurogenesis and hematopoiesis

BAALC 在神经发生和造血中的作用

• 批准号: 6826614
• 负责人: ALBERT DE LA CHAPELLE
• 金额: $ 30.65万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-22 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826614
• 关键词: CD34 molecule; acute leukemia; acute myelogenous leukemia; biomarker; cell differentiation; disease /disorder model; embryogenesis; gene expression; genetically modified animals; hematopoiesis; hematopoietic stem cells; immunocytochemistry; laboratory mouse; model design /development; neoplasm /cancer genetics; neurogenesis; neurogenetics; polymerase chain reaction

DESCRIPTION (provided by applicant): According to the concept of hierarchical cell differentiation somatic stem cells gradually lose their potential to self renew and to produce more than one tissue type. Recently, this concept has been challenged by the demonstration that cells from adult organs may be converted into other tissue types. This phenomenon termed plasticity applies to subsets of cells known as tissue stem cells (TSC). The biology of these TSC is generally poorly understood in part due to the paucity of markers. The overall long-term goal of this proposal is to contribute to a better understanding of the cell differentiation process by determining the role of BAALC, a novel gene, in cell biology. BAALC is expressed in all neuroectodermal tissues including brain tumors, in CD34 positive bone marrow progenitors, and in leukemic blasts from a subset of patients with acute leukemia. In acute myeloid leukemia with normal karyotype, high expression of BAALC independently predicts poor prognosis, suggesting a role in malignancy. To understand the function of BAALC, and to determine whether it serves as a marker both for neurogenic and hematopoietic stem cells and affects their biology, animal modeling in mice will be pursued. Because the structure of BAALC gives no hints about its function, a conventional knockout mouse will be created that will show whether BAALC is vital for embryonic development. Moreover, by examining mice deficient in BAALC it will be determined what cells are mainly affected and at what developmental stage BAALC exerts its function. To specifically determine BAALC's role in neuropoiesis and hematopoiesis conditional, tissue-specific Baalc knockout mice will be generated using the Cre/IoxP recombination technology. These mice will provide insight into Baalc's role in neuropoiesis and hematopoiesis in vivo even in case the conventional knockout condition turns out to be lethal. The mice will be studied immunohistochemically, and by applying various cell lineage-, time-, and developmental stage-specific markers. It is postulated that the high degree of evolutionary conservation of BAALC in mammals will allow observations in mice to be applicable to humans.

描述（由申请人提供）：根据分级细胞分化的概念，体干细胞逐渐失去其自我更新和产生一种以上组织类型的潜力。最近，这一概念受到了来自成人器官的细胞可以转化为其他组织类型的证据的挑战。这种被称为可塑性的现象适用于称为组织干细胞（TSC）的细胞亚群。这些TSC的生物学通常知之甚少，部分原因是缺乏标记物。该提案的总体长期目标是通过确定BAALC（一种新基因）在细胞生物学中的作用，有助于更好地理解细胞分化过程。BAALC在包括脑肿瘤在内的所有神经外胚层组织、CD 34阳性骨髓祖细胞和来自急性白血病患者亚组的白血病原始细胞中表达。在核型正常的急性髓系白血病中，BAALC的高表达独立地预测不良预后，提示在恶性肿瘤中的作用。为了了解BAALC的功能，并确定它是否作为神经源性干细胞和造血干细胞的标志物并影响其生物学，将在小鼠中建立动物模型。由于BAALC的结构没有给出关于其功能的提示，因此将创建一个常规敲除小鼠，以显示BAALC是否对胚胎发育至关重要。此外，通过检查BAALC缺陷的小鼠，将确定哪些细胞主要受到影响以及BAALC在哪个发育阶段发挥其功能。为了特异性地确定BAALC在神经生成和造血条件中的作用，将使用Cre/IoxP重组技术产生组织特异性Baalc敲除小鼠。这些小鼠将提供对Baalc在体内神经生成和造血中的作用的深入了解，即使在常规敲除条件被证明是致命的情况下。小鼠将进行化学研究，并通过应用各种细胞谱系，时间和发育阶段特异性标志物。据推测，BAALC在哺乳动物中的高度进化保守性将使小鼠中的观察结果适用于人类。