HEMATOPOIETIC SPECIFIC GENES IN STEM CELL DEVELOPMENT

一个复杂的监管过程管理着所有 前体干细胞的造血系。对这一点的把握 基本进程将有助于揭示打击的新方法 发育和克隆性血液学疾病，如发育不良 贫血和白血病。干细胞的三个功能特性是 被认可；自我更新，承诺和差异化。寻找 参与这些关键事件的基因导致了对 至少有两类基因：协调的转录因子 基因表达和信号转导。然而，目前还远不清楚 所有关键类别的分子玩家都已经被识别出来，而且它是 很可能是其他种类的基因，目前还未被认识到，参与了 造血干细胞发育。 这个项目的中心目标是扩大对小说的识别 对干细胞的发育和生长很重要的基因。我们的 命题是优先表达的基因 造血细胞将提供一个有价值的研究重点。这 该提案的重点是研究一种名为GDI-D4的新基因。GDI-D4是 在造血发育的非常早期阶段被激活，从 全能干细胞。该基因定位于染色体12p12.3。在白血病中 涉及12p12-13、GDI-D4的非随机缺失的病例位于 所有病例共有的缺失区。GDI-D4可能是肿瘤 抑制者。这种蛋白质的部分功能是GDP解离。 Ras同源蛋白Rho和IS亚家族的抑制物(GDI) 因此，激活和激活周期的关键调节器之一 GTP结合蛋白失活。GDI-D4是为数不多的GDI之一 到目前为止已经确认。 这个项目的具体目标是进一步定义蜂窝和 通过以下步骤研究该基因的生化功能：(1)研究该基因的生物化学功能 胚胎干细胞中该基因的靶向破坏的后果 关于造血细胞发育和功能的研究；(2)鉴定和克隆 利用双杂交酵母研究S蛋白与GDI-D4蛋白的相互作用 系统；(3)进一步研究该化合物的抑瘤活性 蛋白。这些研究应该会使人们更广泛地了解 调节造血的因素。这也可能有助于理解 某些类型白血病的发病机制和 确定治疗干预的潜在靶点。 长期目标是扩大现有知识的范围 造血干细胞发育的分子决定因素及其应用 与人类疾病作斗争的知识。

An intricate regulatory process governs the development of all hematopoietic lineages from precursor stem cells. A grasp of this fundamental process will help to reveal new ways of combating developmental and clonal hematological disorders such as hypoplastic anemias and leukemias. Three functional properties of stem cells are recognized; self-renewal, commitment and differentiation. The search for genes participating in these pivotal events has led to the identification of at least two classes of genes:transcriptional factors that coordinate gene expression and signal transducers. However it is far from clear that all the key classes of molecular players have been identified and it is likely that other classes of gene, as yet unrecognized, are involved in hematopoietic stem cell development. The central goal of this project is to expand the identification of novel genes which are important for development and growth of stem cells. Our proposition is that genes that are preferentially expressed in hematopoietic cells will offer a valuable focus of investigation. This proposal focuses on studying one such novel gene named GDI-D4. GDI-D4 is activated at the very early stages of hematopoietic development from totipotent stem cells. The gene maps to chromosome 12p12.3. In leukemic cases with non-random deletions involving 12p12-13, GDI-D4 resides within a region of deletion common to all cases. GDI-D4 may be a tumor suppressor. The protein functions partially as a GDP-dissociation inhibitor (GDI) of the subfamily of ras homologous proteins, rho, and is therefore one of the key regulators of the cycle of activation and inactivation of GTP binding proteins. GDI-D4 is one of very few GDIs identified so far. The specific aims of this project are to further define the cellular and biochemical function of this gene by the following steps: (1) To study the consequences of a targeted disruption of the gene in embryonal stem cells on hematopoietic cell development and function; (2) To identify and clone for protein(s) interacting with GDI-D4 protein using a double-hybrid yeast system; (3) To further investigate the tumor suppressor activity of this protein. These studies should lead to a broader appreciation of the factors regulating hematopoiesis. It may also help in the understanding of the disease mechanism of certain classes of leukemias and the identification of potential targets for therapeutic intervention. The long term objective is to widen the scope of current knowledge of the molecular determinants of hematopoietic stem cell development and to apply the knowledge in combating human diseases.