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）：根据分层细胞分化的概念，体干细胞逐渐失去了自我更新并产生多种组织类型的潜力。最近，这一概念受到了以下证明，即成年器官的细胞可能会转化为其他组织类型。这种称为可塑性的现象适用于称为组织干细胞（TSC）的细胞子集。这些TSC的生物学通常因缺乏标记而部分理解。该提案的总体长期目标是通过确定一种新基因在细胞生物学中的作用来更好地理解细胞分化过程。 BAALC在包括脑肿瘤，CD34阳性骨髓祖细胞以及来自急性白血病患者子集的所有神经外皮组织中表达。在正常核型的急性髓样白血病中，Baalc的高表达独立预测预后不良，表明在恶性肿瘤中起作用。要了解Baalc的功能，并确定它是否是神经源和造血干细胞的标志物，并影响其生物学，将追求小鼠的动物建模。由于Baalc的结构没有任何有关其功能的提示，因此将创建一种常规的敲除小鼠，该小鼠将显示Baalc是否对胚胎发育至关重要。此外，通过检查缺乏BAALC的小鼠，它将确定主要受影响的细胞，以及在哪个发育阶段Baalc发挥其功能。为了明确确定Baalc在有条件的神经疾病和造血的作用中，将使用CRE/IOXP重组技术生成组织特异性的Baalc敲除小鼠。这些小鼠将洞悉Baalc在体内在体内的作用，即使传统的敲除疾病被证明是致命的，也可以提供体内的作用。通过应用各种细胞谱系，时间和发育阶段特异性标记，将对小鼠进行免疫组织化学研究。据推测，哺乳动物中巴尔克的高度进化保守性将使小鼠的观察适用于人类。