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

基本信息

批准号：
10465011
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
项目类别：
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/10465011
关键词：
Addictive Behavior Amaze Automobile Driving Autophagocytosis Biochemical Biochemical Genetics Biological Models Blindness Cell membrane Cells Cellular Stress Data Deterioration Disease Down-Regulation Drosophila genus Elements Environment Exhibits 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 Stress Synapses System Testing Time Traumatic Brain Injury Vertebrates Visual Visual Acuity Visual system structure arm biological adaptation to stress cell type cellular microvillus circadian experimental study fly genetic approach light intensity mutant nervous system disorder neurotransmission novel protein folding response screening sleep regulation tool visual processing

项目摘要

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.

抽象的神经系统必须适应环境的快速和缓慢变化。一个经典的例子是视觉系统可以适应几个数量级的光照水平变化只需几秒钟。在更长的时间尺度上也观察到了适应，例如光照周期的季节变化。在果蝇中，延长光照时间会触发横纹肌（光感受器的感光细胞器）尺寸的减小，以及下调其突触活跃区。我们最近发现，这一监管结构可塑性取决于未折叠蛋白反应（UPR）。经过仅仅一晚的相处持续光照，UPR 的 IreI 和 PERK 臂都会被激活。干涉 UPR 的正常调节会导致视觉神经传递丧失和严重横纹肌的结构恶化，横纹肌是容纳关键元素的微绒阵列光转导级联。在 fic 和 BiP 突变体中观察到了这种表型干扰 BiP 活性的调节，BiP 是 UPR 的主要调节因子。筛选通过该途径的其他元件，我们鉴定了一种非常规的激酶样蛋白，称为通宵达旦，作为候选人。其序列预测该蛋白可能是一种作用于分泌途径。初步数据表明，与 fic 和 BiP 突变体类似，扩展的光照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。该提案旨在表征调节光感受器的机制结构可塑性以及 Allnighter 在这个过程中的具体作用。具体来说，我们将测试如何调节两个关键的应激途径，即未折叠蛋白反应和自噬，有助于结构可塑性和 Allnighter 蛋白修饰的机制这两条途径。完成这些实验将显着增强我们的能力了解驱动光感受器结构可塑性并维持光感受器结构可塑性的机制长期适应过程中的视力。