Stress induction of a cellular immune response in Drosophila

 描述(申请人提供)：伤害感是一种感觉过程，允许动物检测和避免潜在的有害刺激。这种逃避反应在后生动物中普遍存在，在包括人类在内的非哺乳动物和哺乳动物脊椎动物中也观察到了这种逃逸反应，也在线虫和果蝇等无脊椎动物中观察到了这种逃逸反应。果蝇已经成为研究伤害性感觉遗传学的强大系统，这在很大程度上是由于几种疼痛管理和回避范例的发展。已知的触发伤害性感觉转导的危险刺激包括有毒的高温、有毒的化学物质、紫外线辐射和严酷的机械应力。果蝇也已成为研究包括免疫细胞诱导在内的造血细胞和遗传学基础的优秀系统。血细胞的形成是一个保守的发育过程，在这种模式生物中的造血与人类之间存在着几个相似之处。果蝇体内干细胞样造血祖细胞生态位的发现代表了这一模型系统对干细胞生物学研究的重大贡献。有令人信服的数据支持后部信号中心(PSC)作为幼虫淋巴腺内的小生境的功能，这一区域对于维持正常的血细胞稳态是必不可少的。PSC和存在于淋巴腺髓质区的前血细胞之间的通讯对于控制维持多能状态还是启动血细胞分化程序是至关重要的。这种淋巴腺的细胞组织和分子信号与在几种哺乳动物的造血干细胞壁龛中观察到的非常相似。将伤害性感受和免疫细胞产生的重要过程结合在一起的是我们最近的发现，即对果蝇幼虫施加机械应激可以强有力地诱导淋巴腺造血器官内的血细胞分化。血细胞动态平衡的这种显著变化包括大量产生板层细胞，板层细胞通常被诱导为对黄蜂病原体进入幼虫宿主的保护性细胞免疫反应。值得注意的是，我们的初步发现表明，片层细胞的诱导通过不同的机制发生，以响应机械应激管理和寄生蜂感染。为了更好地理解机械应力诱导这种细胞免疫反应的本质，提出了两个特定的目标。我们计划(1)研究已知在疼痛回避行为中起作用的基因是否也是幼虫对机械应激的细胞免疫反应所必需的；(2)确定调控细胞对动物机械应激的细胞免疫反应的信号通路(S)。总之，这些方法将允许使用果蝇作为一个有价值的模型来研究进化上保守的痛觉和回避遗传学，同时也解决了由于应激暴露而控制免疫细胞诱导的机制。

 DESCRIPTION (provided by applicant): Nociception is the sensory process that allows animals to detect and avoid potentially harmful stimuli. This escape response appears universal in metazoans, being observed in non-mammalian and mammalian vertebrates including humans, also in invertebrates such as nematodes and fruit flies. Drosophila has emerged as a powerful system to study the genetics of nociception, due largely to the development of several pain administration and avoidance paradigms. Hazardous stimuli known to trigger nociception sensory transduction include noxious heat, noxious chemicals, UV-irradiation, and harsh mechanical stress. Drosophila has also emerged as an excellent system to study the cellular and genetic bases of hematopoiesis, including immune cell induction. Blood cell formation is a conserved developmental process and several parallels exist between hematopoiesis in this model organism and humans. The discovery of a stem cell-like hematopoietic progenitor niche in Drosophila represents a highly-significant contribution of this model system to the study of stem cell biology. Compelling data exist to support the belief that the posterior signaling center (PSC) functions as the niche within the larval lymph gland, with this domain essential for maintaining normal blood cell homeostasis. Communication between the PSC and prohemocytes present in the lymph gland medullary zone is crucial for controlling the decision as to maintaining a pluri-potent state versus initiating a hemocyte differentiation program. Such lymph gland cellular organization and molecular signaling is remarkably similar to that observed in the hematopoietic stem cell niches of several mammals. What brings together the vital processes of nociception and immune cell production is our recent discovery that mechanical stress administered to Drosophila larvae results in a robust induction of hemocyte differentiation within the lymph gland hematopoietic organ. This striking change in blood cell homeostasis includes the prodigious production of lamellocytes, cells normally induced as a protective cellular immune response to wasp pathogen introduction into a larval host. It is noteworthy that our preliminary findings suggest that lamellocyte induction occurs via different mechanisms in response to mechanical stress administration versus parasitic wasp infestation. Two Specific Aims are proposed to better comprehend the nature of mechanical stress induction of this cellular immune response. We plan to (1) investigate if genes known to function in pain avoidance behavior are also required for the cellular immune response to larval mechanical stress, and (2) identify the signaling pathway(s) regulating the cellular immune response to animal mechanical stress. Together, these approaches will allow for the use of Drosophila as a valuable model to investigate the evolutionarily conserved genetics of pain sensing and avoidance, while also addressing mechanisms controlling immune cell induction due to stress exposure.