Genetic Dissection of Drosophila Hematopoiesis

描述(由申请人提供)：黑腹果蝇已被公认为是了解包括癌症在内的遗传性疾病的基因功能、发育网络和分子基础的主要遗传模型系统。果蝇的血细胞或血细胞对先天免疫功能以及组织重塑和伤口愈合都很重要。我们启动了果蝇造血的分子遗传学分析，目的是了解这一过程与脊椎动物血液发育和白血病等疾病的关系。我们发现，一个与急性髓系白血病(AML1)蛋白相似的基因对于果蝇一种称为晶体细胞的血细胞类型的发育是必不可少的。这项工作导致了果蝇造血的谱系图，其中显示了几个保守的成分。此外，这种发育的策略与果蝇和脊椎动物造血中涉及的类似信号通路是保守的。更值得注意的是，血管和血细胞(血管母细胞)的共同前体等概念也是保守的。在这项研究中，我们将首先进一步分析在果蝇造血中保守的Notch/PDGF-VEGF受体/JAK-STAT信号通路的功能。我们将开发显微成像方法，在单细胞水平上分析造血过程。我们将找到这种不对称性的分子基础，这种不对称性允许血管母细胞分裂产生混合细胞类型。最后，我们将分析从基因筛查中发现的新基因，并启动新的基因筛查，以确定与果蝇和脊椎动物血细胞成熟有关的前体细胞和可能的干细胞群体以及新蛋白。

DESCRIPTION (provided by applicant): Drosophila melanogaster has been acknowledged as a premier genetic model system for understanding gene function, developmental networks and molecular basis for genetic disorders including cancers. Drosophila has blood cells or hemocytes that are important for innate immune functions as well as tissue remodeling and wound healing. We initiated a molecular genetic analysis of Drosophila hematopoiesis with the goal to understand the relationship of this process to vertebrate blood development and disorders such as Leukemia. We found that a gene sharing similarity to the Acute Myeloid Leukemia (AML1) protein is essential for the development of 1 of the hemocyte types in Drosophila, called crystal cells. This work led to a lineage diagram for Drosophila hematopoiesis that showed several conserved components. Also the strategies for this development are conserved with similar signaling pathways involved in Drosophila and vertebrate hematopoiesis. More remarkably, concepts such as a common precursor for vascular and blood cells (hemangioblasts) are also conserved. In this proposal, we will first further analyze the functions of the conserved Notch/ PDGF-VEGF receptor/JAK-STAT pathways in Drosophila hematopoieis. We will develop microscopic imaging methods to analyze the hematopoietic process at a single cell level. We will find the molecular basis for the asymmetry that allows hemangioblast divisions to create mixed cell types. And finally, we will analyze novel genes identified from a genetic screen and initiate new genetic screens to identify precursor and possibly stem cell populations and novel proteins that are involved in Drosophila and vertebrate blood cell maturation.