Genetic Dissection of Drosophila Hematopoiesis

 描述（由申请人提供）：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具有极大的兴趣和重要性。果蝇长期以来一直作为许多发育过程的遗传模型，但其作为造血模型的有用性直到最近才被认识到。维持果蝇造血干细胞的机制在发育和功能策略上与哺乳动物系统具有显著的保守性。这项研究利用强大的遗传工具和试剂可用于果蝇模型系统，以了解局部和全局信号如何影响血细胞发育。特别是，我们将分析果蝇造血器官内的血细胞分化，以评估 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下受到影响。这项建议包括三个主要目标。目的1描述了旨在映射CO2接收缺陷和血细胞成熟之间的有机体连接的实验。在目标2中，我们提出充分表征血液祖细胞的细胞周期谱，我们将揭示调控蛋白质控制细胞周期进程的信号通路。最后，在目标3中，我们将鉴定和表征上皮组织中肿瘤生长对中胚层衍生的造血器官中血细胞发育的影响。肿瘤负荷对血液/免疫系统的作用对人类癌症和损伤具有重要意义，果蝇为详细了解其机制提供了理想的模型。总的来说，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重要见解，其机制可能在人类中是保守的。PI将参与指导和监督工作，这将涉及4名博士后研究员和1名研究生的培训。此外，该实验室传统上培养了大量的研究本科生。典型的本科生花2-3年在实验室;博士后，5年和研究生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了解，实验室中更有经验的成员将把这种熟悉的知识沿着给新成员。

 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.