Regulation of UV-Induced Apoptosis

描述(申请人提供)：视网膜中的组织动态平衡依赖于在受损细胞的存活和凋亡之间保持精确的平衡。因此，控制细胞对光和紫外线诱导的DNA损伤反应的信号机制在保护视网膜功能方面发挥着关键作用。Jasper实验室使用发育中的果蝇视网膜作为遗传可及的模型系统来研究紫外线诱导的光感受器细胞死亡的调节，从而表征了这种信号机制。在这些研究过程中，已经确定视网膜内稳态不仅由细胞自主机制维持，还由系统信号维持。在这里提供的初步数据中，进一步发现视网膜相关血细胞(血细胞)在促进组织动态平衡方面也发挥着关键作用。在哺乳动物中，组织驻留的巨噬细胞(或小胶质细胞)在促进视网膜的动态平衡方面发挥着重要作用，影响视网膜疾病，包括老年性黄斑变性。然而，支配神经元和巨噬细胞之间相互作用的信号机制才刚刚开始被了解，探索这些机制的合适的遗传模型系统仍然难以捉摸。这项建议引入了果蝇视网膜作为一种可访问的模型来详细研究这种相互作用。该提案所基于的特定初步结果表明，转录因子SchNurri通过调节血细胞功能，是视网膜组织内稳态的关键调节因子。SchNurri在视网膜中发挥作用，促进PDGF和TNF家族的细胞因子的表达，激活视网膜相关的血细胞。这种激活事件反过来又是促进血细胞吞噬活性所必需的，对于在发生基因毒性挑战的情况下保持视网膜的动态平衡是至关重要的。该提案旨在通过(I)表征光感受器中控制细胞因子对DNA损伤的反应的信号事件，(Ii)探索调节血细胞激活的信号通路，以及(Iii)检验血细胞吞噬活性对于防止挑战视网膜过度死亡的假设，从而进一步表征和澄清这一模型。果蝇系统在研究血细胞/视网膜相互作用方面的重要技术优势包括能够以时空精确的方式干扰基因功能，并能够快速和定量地表征所产生的表型。因此，可以预期，我们可以在理解调节视网膜细胞和常驻巨噬细胞之间相互作用的基本信号机制以及这种相互作用对组织健康的影响方面取得重大进展。由于所分析的细胞和分子信号机制是广泛保守的，可以预见，可以获得重要的见解，这将与我们对人类视网膜内稳态控制的理解相关。

DESCRIPTION (provided by applicant): Tissue homeostasis in the retina depends on maintaining a precise balance between survival and apoptosis of damaged cells. Signaling mechanisms that control cellular responses to light and UV-induced DNA damage thus play critical roles in preserving retinal function. The Jasper lab has characterized such signaling mechanisms using the developing Drosophila retina as a genetically accessible model system to study the regulation of UV-induced cell death of photoreceptors. In the course of these studies, it has been established that retinal homeostasis is not only maintained by cell autonomous mechanisms, but also by systemic signals. In preliminary data presented here, it was further found that retina-associated blood cells (hemocytes) also play a critical role in promoting tissue homeostasis. In mammals, tissue-resident macrophages (or microglia) play an important role in promoting homeostasis of the retina, influencing retinal diseases, including age-related macular degeneration. The signaling mechanisms that govern the interaction between neurons and macrophages, however, are only beginning to be understood, and appropriate genetic model systems to explore these mechanisms remain elusive. This proposal introduces the Drosophila retina as an accessible model to study this interaction in detail. The specific preliminary results on which the proposal is based identify the transcription factor Schnurri as a critical regulator of tissue homeostasis in the retina by regulating hemocyte function. Schnurri acts in the retina to promote the expression of cytokines of the PDGF and TNF family that activate retina-associated hemocytes. This activation event, in turn, is required to promote phagocytic activity of hemocytes and is critical for the preservation of retinal homeostasis in the event of a genotoxic challenge. The proposal intends to further characterize and clarify this model, by (i) characterizing signaling events in photoreceptors that control the cytokine response to DNA damage, (ii) exploring the signaling pathways regulating hemocyte activation, and (iii) testing the hypothesis that phagocytic activity of hemocytes is critical to prevent excessive death in the challenged retina. Important technical advantages of the Drosophila system for the study of hemocyte / retina interactions include the ability to perturb gene function with spatiotemporal precision and to characterize resulting phenotypes rapidly and quantitatively. It is thus anticipated that significant progress can be made in our understanding of fundamental signaling mechanisms regulating the interaction between retinal cells and resident macrophages and of the consequences of this interaction for tissue health. Since the analyzed cellular and molecular signaling mechanisms are widely conserved, it can be anticipated that significant insight can be obtained that will be of relevance to our understanding of the control of retinal homeostasis in humans.