Circadian regulation of phagocytosis

描述（由申请人提供）：免疫系统功能的昼夜节律调节鲜为人知，但对人体健康有重大影响。免疫系统功能的许多指标，如细胞因子TNF和IFN- γ的基线水平，随着一天中的时间而变化。昼夜节律调节的丧失也与免疫系统功能低下和对感染的易感性有关。我们已经建立了一个系统来研究果蝇的昼夜调节免疫功能。我们发现，在一天中不同时间感染肺炎链球菌的苍蝇的存活率不同，这是由于昼夜节律调节蛋白的影响。我们进一步确定了一种受昼夜节律调节的特定免疫反应：细菌的吞噬。虽然吞噬作用的细胞生物学在单细胞生物和培养细胞中得到了很好的研究，但在多细胞生物中吞噬作用的分子调控尚不清楚。同样，尽管我们对昼夜节律调节了解很多，但主要的焦点还是集中在分子机制和昼夜节律调节神经元（起搏器神经元）上，而不是效应组织上。我们需要了解相关效应组织的昼夜节律调节，将这些发现转化为医学实践。在初步数据中，我们发现抑制起搏器神经元或吞噬免疫细胞中的昼夜节律调节时钟可增加对肺炎链球菌感染的抵抗力。我们假设起搏器神经元调节吞噬免疫细胞的昼夜节律，决定这些细胞中时钟活动的振荡以及吞噬活动。在本提案中，我们将通过三种方式来检验这一假设：

DESCRIPTION (provided by applicant): Circadian regulation of immune system function is poorly understood but has significant impact on human health. Many measures of immune system function, such as baseline levels of the cytokines TNF and IFN- gamma, vary with time of day. Loss of circadian regulation is also associated with poor immune system function and susceptibility to infection. We have established a system to study circadian-regulated immune function in Drosophila. We found that flies infected at different times of day with S. pneumoniae die with different survival rates and that this is due to the effects of circadian regulatory protens. We further identified a specific immune response that is circadian-regulated: phagocytosis of bacteria. Though the cell biology of phagocytosis is well studied in unicellular organisms and in cultured cells, the molecular regulation of phagocytosis in multicellular organisms is less clear. Similarly, though much is known about circadian regulation, the major focus has been on molecular mechanisms and circadian regulatory neurons (pacemaker neurons)-not on effectors tissues. We need to understand the circadian regulation of relevant effectors tissues to translate these discoveries into medical practice. In preliminary data, we found that inhibition of the circadian regulator Clock in either pacemaker neurons or phagocytic immune cells increases resistance to infection by S. pneumoniae. We hypothesize that pacemaker neurons regulate the circadian rhythms of phagocytic immune cells, dictating the oscillation of Clock activity in those cells as well as phagocytic activity. In this proposal, we will test this hypothesis in three ways: we will identify cellular mechanisms underlying circadian-regulated phagocytosis (Aim 1); we will also examine how cell-autonomous circadian regulators control phagocyte function (Aim 2) and how pacemaker neurons non cell-autonomously regulate phagocyte function (Aim 3). Thus the proposed experiments will analyze circadian regulation of immune system function on molecular, cellular, and systemic levels. Because of the high evolutionary conservation of both innate immunity and circadian biology, defining the molecular mechanisms in Drosophila will provide insight into ways to improve human innate immune system function.