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）：视网膜中的组织稳态取决于维持受损细胞的存活和凋亡之间的精确平衡。因此，控制细胞对光和紫外线引起的 DNA 损伤的反应的信号机制在保护视网膜功能方面发挥着关键作用。贾斯珀实验室利用正在发育的果蝇视网膜作为遗传上可访问的模型系统来表征这种信号传导机制，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由细胞自主机制维持，而且还由系统信号维持。在此提供的初步数据中，进一步发现视网膜相关血细胞（血细胞）在促进组织稳态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）在促进视网膜稳态、影响视网膜疾病（包括年龄相关性黄斑变性）方面发挥着重要作用。然而，控制神经元和巨噬细胞之间相互作用的信号传导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。该提案引入了果蝇视网膜作为详细研究这种相互作用的可访问模型。该提案所依据的具体初步结果确定转录因子 Schnurri 通过调节血细胞功能作为视网膜组织稳态的关键调节因子。 Schnurri 在视网膜中发挥作用，促进 PDGF 和 TNF 家族细胞因子的表达，从而激活视网膜相关血细胞。反过来，这种激活事件是促进血细胞吞噬活性所必需的，并且对于在基因毒性攻击时维持视网膜稳态至关重要。该提案旨在进一步表征和阐明该模型，通过（i）表征控制细胞因子对 DNA 损伤反应的光感受器中的信号传导事件，（ii）探索调节血细胞活化的信号传导途径，以及（iii）测试吞噬细胞活性的假设血细胞的减少对于防止受挑战的视网膜过度死亡至关重要。果蝇系统用于研究血细胞/视网膜相互作用的重要技术优势包括能够以时空精度扰乱基因功能并快速定量地表征所得表型。因此，预计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可以取得重大进展。由于所分析的细胞和分子信号传导机制广泛保守，因此可以预期可以获得重要的见解，这将有助于我们理解人类视网膜稳态的控制。