Role of stress responses in regulating photoreceptor structural plasticity

应激反应在调节感光器结构可塑性中的作用

• 批准号: 10614036
• 负责人: Helmut J Kramer
• 金额: $ 36.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614036
• 关键词: Addictive Behavior; Amaze; Automobile Driving; Autophagocytosis; Biochemical; Biological Models; Blindness; Cell membrane; Cells; Cellular Stress; Darkness; Data; Deterioration; Disease; Down-Regulation; Drosophila genus; Elements; Environment; Exhibits; Experimental Genetics; Genes; Genetic; Goals; Health; Light; Link; Maintenance; Malignant Neoplasms; Measures; Membrane Proteins; Molecular; Morphology; Nerve Degeneration; Neurons; Organelles; Pathology; Pathway interactions; Personal Satisfaction; Phenocopy; Phenotype; Phosphotransferases; Photoreceptors; Phototransduction; Physiological; Play; Process; Proteins; Regulation; Role; Seasons; Stress; Synapses; System; Testing; Time; Traumatic Brain Injury; Vertebrates; Visual; Visual Acuity; Visual System; arm; biological adaptation to stress; cell type; cellular microvillus; circadian; experimental study; fly; genetic approach; light intensity; mutant; nervous system disorder; neurotransmission; novel; response; screening; sleep regulation; tool; visual processing

Abstract Neuronal systems must adapt to fast and slow changes in the environment. A classic example is the visual system which can adjust to changes in several orders of magnitude in light levels within just seconds. Adaptation has also been observed on a much longer time scale, such as seasonal changes in the light period. In Drosophila, shifts to an extended light period trigger a reduction in the size of rhabdomeres, the light-sensitive organelle of photoreceptors, and a down regulation of their synaptic active zones. We recently discovered that regulation of this structural plasticity depends on the unfolded protein response (UPR). After just one night with continued light exposure, both the IreI and the PERK arm of the UPR are activated. Interference with the normal regulation of the UPR results in the loss of visual neurotransmission and severe structural deterioration of rhabdomeres, the microvillar arrays that house the key elements of the phototransduction cascade. This phenotype was observed for fic and BiP mutants that interfere with the regulation of the activity of BiP, a major regulator of the UPR. Screening for additional elements of this pathway, we identified an unconventional kinase-like protein, called Allnighter, as a candidate. Its sequence predict that this protein may be a kinase acting in the secretory pathway. Preliminary data indicate that, similar to fic and BiP mutants, an extended light period causes allnighter mutants to lose visual neurotransmission and structural integrity of rhabdomeres. This proposal aims to characterize the mechanisms regulating photoreceptor structural plasticity and the specific role of Allnighter in this process. Specifically, we will test how regulation of two key stress pathways, the unfolded proteins response and autophagy, contributes to structural plasticity and the mechanisms by which the Allnighter protein modifies both of these pathways. Completion of these experiments will significantly enhance our understanding of the mechanism that drive structural plasticity of photoreceptors and maintain visual acuity during long-term adaptation.

摘要 神经元系统必须适应环境的快速和缓慢变化。一个典型的例子是 视觉系统可以根据光照水平的几个数量级的变化进行调整 几秒钟之内。在更长的时间尺度上也观察到了适应，例如 光周期的季节变化。在果蝇中，长时间的光照会触发 感受器的光敏感细胞器--横纹肌的体积缩小， 突触活性区的下调。我们最近发现， 结构可塑性取决于未折叠蛋白反应（UPR）。仅仅一晚之后， 持续曝光，UPR的IreI和PERK臂都被激活。干扰 UPR的正常调节导致视觉神经传递的丧失， 横纹肌的结构恶化，横纹肌是容纳细胞关键元件的微绒毛阵列 光传导级联。在fic和BiP突变体中观察到这种表型， 干扰BiP活性的调节，BiP是UPR的主要调节剂。筛查 在这一途径的其他元件中，我们发现了一种非常规的激酶样蛋白，称为 作为候选人，通宵达旦。其序列预测该蛋白可能是一种激酶， 分泌途径初步数据表明，类似于fic和BiP突变体， 光周期导致通宵突变体失去视觉神经传递和结构完整性 横纹肌该建议旨在描述调节感光细胞的机制 结构可塑性和通宵在这一过程中的具体作用。具体来说，我们将测试 如何调节两个关键的应激途径，未折叠蛋白反应和自噬， 有助于结构可塑性和通宵蛋白质修饰的机制， 这两种途径。这些实验的完成将大大提高我们的 理解驱动光感受器结构可塑性的机制， 长期适应期的视力。