Regulation of UV-induced apoptosis

紫外线诱导细胞凋亡的调节

• 批准号: 7373297
• 负责人: Heinrich Jasper
• 金额: $ 22.29万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373297
• 关键词: Address; Age related macular degeneration; Apoptosis; Apoptotic; Biochemical Genetics; Biological Models; Boxing; Cell Death; Cell Fate Control; Cell Survival; Cell model; Cells; Cessation of life; DNA Damage; Data; Degenerative Disorder; Disease; Dominant Genetic Conditions; Dose; Drosophila genus; Ensure; Environment; Equilibrium; Event; Eye; Feedback; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Screening; Homeostasis; Insulin Receptor; Life; MAPK8 gene; Malignant Neoplasms; Mediating; Modeling; Molecular Profiling; N-terminal; Nuclear; Organism; Pathway interactions; Phase; Phosphotransferases; Play; Post-Translational Protein Processing; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Retina; Retinal; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; Stimulus; Stress; System; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Transcriptional Regulation; UV induced; UV induced DNA damage; UV response; base; biological adaptation to stress; cell growth regulation; cell injury; combinatorial; design; fly; gene repair; in vivo; insight; prevent; programs; promoter; repaired; research study; response; tool; transcription factor; ultraviolet irradiation

DESCRIPTION (provided by applicant): To ensure tissue homeostasis in multicellular organisms, cells damaged by environmental insults (such as UV irradiation) have to be either repaired or eliminated. Misregulation of the decision between cell repair and cell death plays an important role in degenerative diseases of the retina, such as age-related macular degeneration, as well as more generally in cancer. Insight into the regulation of cellular damage defense and cell death will increase our ability to prevent and/or treat such diseases. Current models suggest that the balance between cell survival signals and pro-apoptotic stimuli controls the decision between repair and death of a cell. How these competing signals are integrated and interpreted to achieve accurate control over cell fate in vivo is incompletely understood. Studies using genetically accessible model systems are required to gain further insight into this regulatory system. The applicant has performed preliminary studies to analyze the regulation of cellular life-death decisions in the retina. These studies show that the Forkhead Box O transcription factor Foxo as well as the AP-1 transcription factor DFos are required downstream of the Jun-N-terminal Kinase signaling pathway for the apoptotic response to UV-induced DNA damage in the developing Drosophila retina. Importantly, these studies show that UV-induced apoptosis is repressed by survival signals emanating from Receptor Tyrosine Kinase pathways, which are known to inactivate Foxo. These data suggest that integrating stress and survival signals through Foxo drives the decision between cell death and repair of damaged cells in vivo. This model will be tested by addressing the following specific aims experimentally: (i) Analyze the regulation of UV-induced transcriptional responses in the retina. Using expression profiling approaches, the regulation of pro-apoptotic and pro-survival gene expression programs will be analyzed in the retina. (ii) Test whether biphasic activation of JNK signaling governs the cellular response to UV. The applicant proposes that JNK activation in response to UV stress occurs in two phases: an initial phase that promotes cell recovery and, when DNA damage persists, a second phase that induces pro-apoptotic gene expression. Genetic experimentation will be used to test this model. (iii) Identify regulators of the retinal UV response using genetic approaches. One advantage of the Drosophila system is the ability to use genetic screens to rapidly identify new components of signaling pathways. Here, such approaches will be used to identify new genes that will allow addressing specific questions regarding the control of cell fate and signaling specificity. The experiments proposed here are expected to significantly advance our understanding of the regulation of cellular life/death decisions in intact tissues and will therefore be of relevance to future rational therapeutic approaches for degenerative diseases.

描述（由申请人提供）：为了确保多细胞生物体的组织稳态，必须修复或消除因环境侵害（例如紫外线照射）而受损的细胞。细胞修复和细胞死亡之间决策的错误调节在视网膜退行性疾病（例如与年龄相关的黄斑变性）以及更常见的癌症中发挥着重要作用。对细胞损伤防御和细胞死亡调节的深入了解将提高我们预防和/或治疗此类疾病的能力。 目前的模型表明，细胞存活信号和促凋亡刺激之间的平衡控制着细胞修复和死亡之间的决定。如何整合和解释这些竞争信号以实现对体内细胞命运的精确控制尚不完全清楚。需要使用遗传可访问模型系统进行研究，以进一步了解该调节系统。 申请人已经进行了初步研究来分析视网膜细胞生死决定的调节。这些研究表明，Forkhead Box O 转录因子 Foxo 以及 AP-1 转录因子 DFos 是 Jun-N 末端激酶信号通路下游所必需的，以对发育中的果蝇视网膜中紫外线诱导的 DNA 损伤做出细胞凋亡反应。重要的是，这些研究表明，紫外线诱导的细胞凋亡受到受体酪氨酸激酶途径发出的生存信号的抑制，已知该途径可以使 Foxo 失活。这些数据表明，通过 Foxo 整合压力和生存信号可以驱动体内受损细胞的死亡和修复之间的决定。该模型将通过实验解决以下具体目标进行测试：（i）分析视网膜中紫外线诱导转录反应的调节。使用表达谱方法，将分析视网膜中促凋亡和促生存基因表达程序的调节。 (ii) 测试 JNK 信号传导的双相激活是否控制细胞对紫外线的反应。申请人提出，响应紫外线应激的 JNK 激活分两个阶段进行：促进细胞恢复的初始阶段，以及当 DNA 损伤持续存在时，诱导促凋亡基因表达的第二阶段。遗传实验将用于测试该模型。 (iii) 使用遗传方法确定视网膜紫外线反应的调节因子。果蝇系统的优势之一是能够利用遗传筛选快速识别信号通路的新成分。在这里，此类方法将用于识别新基因，从而解决有关细胞命运控制和信号特异性的具体问题。 这里提出的实验预计将显着增进我们对完整组织中细胞生命/死亡决策调节的理解，因此与未来退行性疾病的合理治疗方法相关。