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非常有趣和重要。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用途直到最近才得到重视。维持果蝇造血干细胞的机制在哺乳动物系统的发育策略和功能上具有显著的保守性。提出的工作旨在确定维持干细胞稳态的分子途径。还提出了系统信号和营养剥夺在髓细胞发育中的作用。这些都是与发育和医学相关的问题，因此开发适合基因筛选的模型系统至关重要。该提案有四个具体目标。在Aim 1中，将建立一个稳态模型，通过该模型，血液前体不仅由来自生态位的信号维持，而且还来自已经开始分化的细胞。在Aim 2中，将研究转录因子STAT在果蝇干细胞命运维持中的作用。在Aim 3中，将研究控制干细胞完整性的细胞外基质成分的作用。在最后的目的中，将研究控制果蝇血液干细胞维持的来自大脑的信号，并研究它们在饥饿诱导的干细胞损失中的作用。

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 leukemias. 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. The proposed work intends to determine the molecular pathways that maintain stem cell homeostasis. Also proposed is the role of systemic signals and nutrient deprivation on myeloid cell development. These are developmentally and medically relevant problems for which model systems amenable to genetic screens are essential to develop. The proposal has four specific aims. In Aim 1, a homeostatic model by which blood precursors are maintained not only by a signal from a niche, but also from the cells that have started differentiating will be developed. In Aim 2, the involvement of the transcription factor STAT in the maintenance of stem cell fate in Drosophila will be investigated. In Aim 3, the role of extracellular matrix components that control the integrity of stem cells will be studied. In the final aim, signals arising from the brain that control blood stem cell maintenance in Drosophila will be investigated and their role in starvation induced stem cell loss studied. PUBLIC HEALTH RELEVANCE: The genetic basis of blood development and disorders are extremely important to understand in order to make progress on understanding immune challenges and leukemias. The fruit fly, Drosophila is a model organism in which such studies can be achieved with great predictive power for the human condition. This proposal seeks to understand the molecular mechanisms by which blood stem cells are maintained, and also how these cells respond to stresses that result from starvation.