Genetic Dissection of Drosophila Hematopoiesis

 描述(申请人提供)：从理解正常功能和白血病的角度来看，血液发育和疾病的分子机制是非常感兴趣和重要的。长期以来，果蝇一直是许多发育过程的遗传模型，但它作为造血模型的有用性直到最近才被认识到。果蝇维持血液干细胞的机制在发育策略和与哺乳动物系统的功能上显示出显着的保守性。这项研究利用可用于果蝇模型系统的强大的遗传工具和试剂来了解局部和全球信号如何影响血细胞发育。特别是，我们将分析果蝇血液生成器官内的血细胞分化，以评估如何 细胞周期、细胞分化和器官形态在正常发育过程中以及在应激环境刺激存在的情况下都会受到影响。这项建议包括三个主要目标。目的1描述了旨在绘制二氧化碳接收缺陷和血细胞成熟之间的生物联系的实验。在目标2中，我们建议全面描述造血祖细胞的细胞周期特征，并揭示调控细胞周期进程的蛋白的信号通路。最后，在目标3中，我们将识别和表征上皮组织中肿瘤生长对中胚层来源的造血器官中的血细胞发育的影响。肿瘤负荷对血液/免疫系统的作用在人类癌症和损伤中具有重要意义，果蝇为详细了解其作用机制提供了理想的模型。总体而言，我们提出的研究将导致对血细胞如何受到外部和内部刺激的影响的关键见解，其中的机制可能在人类身上保存下来。PI将参与指导和监督将涉及培训4名博士后研究员和1名研究生的工作。此外，该实验室传统上培养大量的本科生进行研究。典型的本科生在实验室工作2-3年，博士后5年，研究生5-6年。我们研究的主要科学学科包括发育生物学和遗传学。所有参与的研究生和博士后研究人员在这两个领域都非常有知识，实验室中经验更丰富的成员将把这种熟悉传递给新成员。

 DESCRIPTION (provided by applicant): Molecular mechanisms underlying blood development and disorders are of great interest and importance from the perspective of understanding normal function and leukemia. Drosophila has long served as a genetic model for many developmental processes, but its usefulness as a hematopoietic model has only recently been appreciated. The mechanisms that maintain blood stem cells in Drosophila show remarkable conservation in strategy of development and function with mammalian systems. This study utilizes powerful genetic tools and reagents available for the Drosophila model system to understand how local and global signals affect blood cell development. In particular, we will analyze blood cell differentiation within the fruit fly blood-producing organ to assess how cell cycle, cell differentiation, and organ morphology are influenced during normal development as well as in the presence of stressful environmental stimuli. This proposal consists of three major aims. Aim 1 describes experiments aimed at mapping the organismal connection between defects in CO2 reception and blood cell maturation. In Aim 2 we propose to fully characterize the cell cycle profile of blood progenitors and we will uncover the signaling pathways regulating proteins controlling cell cycle progression. Finally, in Aim 3, we will identify and characterize te effects of tumor growth in epithelial tissue on blood cell development in the mesoderm derived hematopoietic organ. The role of tumor burden on the blood/immune system is of great importance to human cancer and injury, and Drosophila provides an ideal model for understanding the mechanisms in detail. Overall, the research we propose will lead to critical insights into how blood cells are influenced by external and internal stimuli, the mechanisms of which are likely to be conserved in humans. The PI will be involved in mentoring and supervision of the work that will involve the training of 4 postdoctoral fellows and 1 graduate student. Additionally, the laboratory traditionally trains a large number of undergraduates in research. The typical undergraduate spends 2-3 years in the laboratory; postdocs, 5 years and graduate students 5-6 years. The main scientific disciplines our research encompasses include developmental biology and genetics. All graduate and postdoctoral researchers involved are extremely knowledgeable in these two fields, and the more experienced members of the lab will pass along this familiarity to newer members.