Regulation of UV-Induced Apoptosis

紫外线诱导细胞凋亡的调节

• 批准号: 8511654
• 负责人: Heinrich Jasper
• 金额: $ 46.08万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511654
• 关键词: Address; Adhesiveness; Age related macular degeneration; Apoptosis; Biological Models; Biological Preservation; Blood Cells; Cell Adhesion; Cell Death; Cell Survival; Cells; Cessation of life; Communication; Cytokine Gene; DNA Damage; Data; Degenerative Disorder; Drosophila genus; Ensure; Equilibrium; Event; Family; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Growth Factor; Health; Hemocytes; Homeostasis; Homologous Gene; Human; Inflammatory; Lead; Light; MAPK8 gene; Maintenance; Mammals; Mediating; Microglia; Modeling; Molecular; Morphology; Neurons; Neuroprotective Agents; Pathway interactions; Phagocytosis; Phenotype; Photoreceptors; Platelet-Derived Growth Factor; Play; Process; Recovery; Recruitment Activity; Regulation; Retina; Retinal; Retinal Diseases; Role; Secretory Cell; Signal Pathway; Signal Transduction; System; TNF gene; Testing; Time; Tissues; Tumor Necrosis Factor Receptor; UV induced; UV induced DNA damage; UV response; Vertebrates; Work; Zinc Fingers; base; cell injury; cell motility; computerized data processing; cytokine; gene function; genetic manipulation; injured; insight; macrophage; neurotrophic factor; prevent; programs; repaired; response; spatiotemporal; transcription factor; ultraviolet damage; ultraviolet irradiation

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.

描述（由申请人提供）：视网膜的组织稳态依赖于维持受损细胞存活和凋亡之间的精确平衡。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中起着关键作用。Jasper实验室利用发育中的果蝇视网膜作为遗传可接近的模型系统，表征了这种信号机制，以研究紫外线诱导的光感受器细胞死亡的调节。在这些研究过程中，已经确定视网膜稳态不仅是由细胞自主机制维持的，而且是由系统信号维持的。在这里提供的初步数据中，进一步发现视网膜相关的血细胞（血细胞）在促进组织稳态中也起着关键作用。在哺乳动物中，组织内巨噬细胞（或小胶质细胞）在促进视网膜稳态中发挥重要作用，影响视网膜疾病，包括年龄相关性黄斑变性。然而，控制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理解，并且探索这些机制的适当遗传模型系统仍然难以捉摸。这一建议引入果蝇视网膜作为一个可访问的模型来详细研究这种相互作用。该提案所基于的具体初步结果确定了转录因子Schnurri是通过调节血细胞功能来调节视网膜组织稳态的关键因子。Schnurri在视网膜中促进激活视网膜相关血细胞的PDGF和TNF家族细胞因子的表达。这种激活事件反过来又需要促进血细胞的吞噬活性，并且对于在基因毒性攻击事件中保持视网膜稳态至关重要。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）验证血细胞吞噬活性对防止受损视网膜过度死亡至关重要的假设，进一步表征和阐明该模型。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度干扰基因功能，并能够快速定量地表征结果表型。因此，可以预期，在我们对调节视网膜细胞和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的理解方面可以取得重大进展。由于所分析的细胞和分子信号机制是广泛保守的，可以预期，可以获得重要的见解，这将与我们对人类视网膜稳态控制的理解相关。