BAALC in neurogenesis and hematopoiesis

描述(申请人提供)：根据分层细胞分化的概念，体细胞干细胞逐渐失去自我更新和产生多种组织类型的潜力。最近，这一概念受到了挑战，因为有证据表明，来自成人器官的细胞可能会转化为其他组织类型。这种被称为可塑性的现象适用于被称为组织干细胞(TSC)的细胞亚群。对这些TSC的生物学一般知之甚少，部分原因是缺乏标记物。这项建议的总体长期目标是通过确定BAALC这一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、CD34阳性的骨髓前体细胞和部分急性白血病患者的白血病细胞中都有表达。在核型正常的急性髓系白血病中，BAALC的高表达独立地预示着不良的预后，提示BAALC在恶性变中起作用。为了了解BAALC的功能，并确定它是否同时作为神经性和造血性干细胞的标志并影响它们的生物学，我们将进行小鼠的动物模型。由于BAALC的结构没有给出其功能的任何线索，因此将创建一个传统的基因敲除小鼠，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BAALC主要受影响的细胞以及BAALC在什么发育阶段发挥其功能。为了具体确定BAALC在神经生成和造血条件下的作用，将使用Cre/IoxP重组技术产生组织特异性Baalc基因敲除小鼠。这些小鼠将深入了解Baalc在体内神经生成和造血中的作用，即使在传统的基因敲除条件被证明是致命的情况下也是如此。将对小鼠进行免疫组织化学研究，并应用各种细胞谱系、时间和发育阶段特定的标记物。据推测，BAALC在哺乳动物中的高度进化保守性将使在老鼠身上的观察适用于人类。

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.