Genetic Dissection of Drosophila Hematopoiesis

描述（由申请人提供）：黑腹果蝇被认为是理解基因功能、发育网络和遗传疾病包括癌症的分子基础的首要遗传模型系统。果蝇的血细胞或血细胞对先天免疫功能、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）蛋白相似的基因对果蝇中一种血细胞类型（称为晶体细胞）的发育至关重要。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，这种发展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，诸如血管细胞和血细胞的共同前体（血管母细胞）等概念也被保留下来。在本提案中，我们将首先进一步分析保守的Notch/ PDGF-VEGF受体/JAK-STAT通路在果蝇造血中的功能。我们将开发显微镜成像方法来分析造血过程在单细胞水平。我们将找到不对称的分子基础，使成血管细胞分裂产生混合的细胞类型。最后，我们将分析从遗传筛选中鉴定出的新基因，并启动新的遗传筛选，以鉴定参与果蝇和脊椎动物血细胞成熟的前体和可能的干细胞群体和新蛋白质。

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.