BAALC in neurogenesis and hematopoiesis

描述（由申请人提供）：根据细胞分层分化的概念，体细胞逐渐失去自我更新和产生多种组织类型的潜力。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明的挑战。这种被称为可塑性的现象适用于被称为组织干细胞（TSC）的细胞子集。由于缺乏标记物，这些TSC的生物学通常知之甚少。本研究的长期目标是通过确定新基因BAALC在细胞生物学中的作用，为更好地理解细胞分化过程做出贡献。BAALC在包括脑肿瘤在内的所有神经外胚层组织、CD34阳性骨髓祖细胞和部分急性白血病患者的白血病母细胞中表达。在核型正常的急性髓系白血病中，BAALC的高表达独立预测预后不良，提示其在恶性肿瘤中起作用。为了了解BAALC的功能，并确定它是否作为神经源性和造血干细胞的标记物并影响其生物学，将在小鼠中进行动物建模。由于BAALC的结构没有提示其功能，因此将创建常规敲除小鼠，以显示BAALC是否对胚胎发育至关重要。此外，通过检测BAALC缺乏的小鼠，可以确定哪些细胞主要受到影响，以及BAALC在哪个发育阶段发挥作用。为了明确确定BAALC在神经生成和造血条件中的作用，将使用Cre/IoxP重组技术生成组织特异性BAALC敲除小鼠。这些小鼠将提供Baalc在体内神经生成和造血中的作用，即使传统的敲除条件被证明是致命的。将对小鼠进行免疫组织化学研究，并应用各种细胞谱系、时间和发育阶段特异性标记。据推测，哺乳动物中BAALC的高度进化保守性将使小鼠的观察结果适用于人类。

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.