Genomic and Genetic Dissection of Hematopoietic Development in Drosophila

项目摘要/摘要 阐明支持正常血细胞发育的遗传和分子机制是一种 了解和治疗白血病等造血系统疾病的重要前提。果蝇 已经被证明是一种非常强大的系统，可以用来对这种机制进行遗传解剖，这些机制是 在哺乳动物中非常保守。这项研究使用了果蝇中可用的优秀遗传工具 解决与如何实现祖细胞和分化细胞之间的平衡有关的具体问题。 初步数据表明，细胞周期调控和分化途径之间的紧密耦合 祖细胞在决定祖细胞和分化细胞的平衡中起着重要作用。在……里面 此外，起源于不同暂时性群体的两个信号定义了平行的造血路径 发展，我们假设它们随后会影响祖细胞维持之间的平衡 和分化，这对动态平衡至关重要。这些机制将从三个方面进行探讨。在目标1中， 彻底的遗传分析将旨在获得时空发育的证据 在造血过程中产生平行路径的机制。基因数据将被完全整合 通过转录分析来确定系统是如何在相关的细胞中产生谱系偏见的，但是 不是一模一样的抄本。在目标2中，区分这两个短暂群体的信号将是 将探讨这些信号对祖细胞维持和平衡的下游影响 差异化。这将涉及到对JNK相关和PVR相关信号的遗传解剖，这两个信号是 每个短暂种群的独特属性。最后，在目标3中，对整合的HH-1进行了遗传/功能分析。 而控制细胞增殖和分化之间平衡的依赖于Wnt6的途径将是 调查过了。WNT6在控制细胞生长和祖细胞氧化状态方面的作用将被测试为 从机制上理解细胞周期和分化的控制是如何以及为什么是密切和 直接联系在一起。总体而言，拟议的研究将产生对基本情况的重要见解 控制祖细胞维持和维持的对立力量之间的平衡的机制 血细胞发育中的分化。由于这些通路在人类中是保守的，因此这一分析将有所帮助 弥合了广泛可用的关于造血过程中基因控制的描述之间的差距 这种遗传网络与受控的造血过程在体内的明确功能相关性 在动态平衡状态和导致血液紊乱的遗传扰动期间。这些实验， 在果蝇模型中所做的，将进一步加深我们对未来分析的理解，并为其提供指导 人类的血液发育和疾病。

PROJECT SUMMARY/ABSTRACT Elucidation of the genetic and molecular mechanisms that underlie normal blood cell development is an important prerequisite for understanding and treating hematopoietic disorders such as leukemias. Drosophila has proven to be an extremely powerful system for genetic dissection of such mechanisms, which are remarkably conserved in mammals. This study uses the excellent genetic tools available in Drosophila to address specific questions related to how the balance between progenitors and differentiated cells is achieved. Preliminary data suggests that the tight coupling between cell-cycle regulation and differentiation pathways in progenitors plays an important role in determining the balance of progenitors and differentiated cells. In addition, two signals that originate in distinct transitory populations define parallel paths of hematopoietic development, and we hypothesize that they subsequently affect the balance between progenitor maintenance and differentiation that is crucial for homeostasis. These mechanisms will be explored in three aims. In Aim 1, a thorough genetic analysis will be aimed towards obtaining evidence for the spatiotemporal developmental mechanisms that generate parallel paths in hematopoiesis. The genetic data will be fully integrated with transcriptomic analysis to determine how the system generates lineage biases in cells with related, but not identical transcriptomes. In Aim 2, the signals that distinguish the two transitory populations will be explored as will the downstream effects of these signals on the balance between progenitor maintenance and differentiation. This will involve the genetic dissection of a JNK-related and a PVR-related signal that are unique attributes of each transitory population. Lastly, in Aim 3, a genetic/functional analysis of integrated Hh- and Wnt6-dependent pathways that control the balance between cell proliferation and differentiation will be investigated. The role of Wnt6 in controlling cell growth and oxidative status of the progenitors will be tested to obtain a mechanistic understanding of how and why the control of cell cycle and differentiation are closely and directly linked to each other. Overall, the proposed research will yield important insights into the fundamental mechanisms that govern the balance between the opposing forces of progenitor maintenance and differentiation in blood cell development. As these pathways are conserved in humans, this analysis will help bridge the gap between broadly available descriptions of genetic control during hematopoiesis with the less well-defined in vivo functional relevance of such genetic networks to the controlled process of hematopoiesis during homeostatic conditions and the genetic perturbations that lead to blood disorders. These experiments, done in the Drosophila model, will further our understanding of, and provide guidance for, future analysis of blood development and disorders in humans.