Stress induction of a cellular immune response in Drosophila

 描述（由申请人提供）：伤害感受是允许动物检测和避免潜在有害刺激的感觉过程。这种逃避反应似乎普遍存在于后生动物中，在非哺乳动物和哺乳动物脊椎动物（包括人类）中观察到，也在无脊椎动物（如线虫和果蝇）中观察到。果蝇已经成为一个强大的系统来研究伤害感受的遗传学，主要是由于几个疼痛管理和回避范式的发展。已知触发伤害感受感觉转导的危险刺激包括有害热、有害化学物质、UV照射和苛刻的机械应力。 果蝇也成为研究造血（包括免疫细胞诱导）的细胞和遗传基础的优秀系统。血细胞形成是一个保守的发育过程，在这种模式生物体和人类的造血之间存在几个相似之处。在果蝇中发现的干细胞样造血祖细胞生态位代表了该模型系统对干细胞生物学研究的高度重要贡献。令人信服的数据存在，以支持的信念，后部信号中心（PSC）的功能作为小生境内的幼虫淋巴腺，与这个域是必不可少的维持正常的血细胞稳态。PSC和淋巴腺髓区中存在的原血细胞之间的通信对于控制维持多能状态与启动血细胞分化程序的决定至关重要。这种淋巴腺细胞组织和分子信号传导与在几种哺乳动物的造血干细胞小生境中观察到的非常相似。 我们最近发现，给予果蝇幼虫的机械应力导致淋巴腺造血器官内血细胞分化的强烈诱导，这将伤害感受和免疫细胞产生的重要过程结合在一起。这种血细胞内稳态的显著变化包括片状细胞的大量产生，片状细胞通常作为对黄蜂病原体引入幼虫宿主的保护性细胞免疫反应而诱导。值得注意的是，我们的初步研究结果表明，片状细胞诱导发生通过不同的机制，在响应机械应力管理与寄生蜂侵扰。 提出了两个具体目标，以更好地理解机械应力诱导这种细胞免疫反应的性质。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，以及（2）确定调节动物对机械应激的细胞免疫反应的信号通路。总之，这些方法将允许使用果蝇作为一个有价值的模型，以调查进化上保守的遗传学的疼痛感测和回避，同时也解决机制控制免疫细胞诱导由于压力暴露。

 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.