Social Interaction in Neuroprotection and Lifespan of Drosophila SOD Mutants

果蝇 SOD 突变体的神经保护和寿命中的社会互动

基本信息

批准号：
8683660
负责人：
CHUN-FANG WU
金额：
$ 22.6万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8683660
关键词：
Adopted Adult Aerobic Aging Aging-Related Process Amyotrophic Lateral Sclerosis Animals Behavioral Cell physiology Characteristics Collection Cuprozinc Superoxide Dismutase Data Disease Drosophila genus Employee Strikes Environmental Risk Factor Enzymes Event Genes Genetic Health Homologous Gene Housing Human Individual Intervention Investigation Ion Channel Link Longevity Maps Membrane Metabolic Metabolic Pathway Metabolism Microarray Analysis Modification Molecular Genetics Motor Nature Nervous System Physiology Nervous system structure Neurodegenerative Disorders Neurons Oxidation-Reduction Phenotype Physiological Process Property Quality of life Reactive Oxygen Species Regulation Resistance Role Sensory Social Interaction Stress Superoxide Dismutase System Techniques Western Blotting biological adaptation to stress cellular imaging fly gene environment interaction improved interest mutant neural circuit neuronal excitability neuroprotection public health relevance research study sensorimotor system social stressor tool

项目摘要

DESCRIPTION (provided by applicant): We found a striking, robust life-span extension effect of social interaction in Drosophila Sod mutants defective in Cu/Zn superoxide dismutase (SOD). Lacking SOD enzymatic activity hampers the ability of animals to clear the harmful reactive oxygen species (ROS) generated in aerobic metabolic process, leading to accelerated aging and excessive stress responses, and is implicated in several neurodegenerative diseases. We found that upon co-housing with younger or more active flies, Sod mutants display not only a doubled lifespan, but also improved stress-resistance and motor coordination. These phenotypes provide a sensitized system for intervention and for unraveling the interacting genetic networks and metabolic pathways underlying certain neuroprotective mechanisms and lifespan determination. We will adopt a multi-disciplinary approach with the molecular, genetic, physiological and behavioral tools developed in our lab and collaborators to facilitate correlation within the same individual or groups of flies subjected to studies at different levels. Aim1: To refine the behavioral experiments to reveal the nature of beneficial behavioral interactions for further understanding of the neuroprotective effect of social interaction in Sod flies. We aim to use the automated video tracking system, IowaFLI Tracker, newly developed in our lab in conjunction with other standard behavioral techniques. Aim2: Sod flies with or without co-housed helpers will be examined for key redox enzymes or their substrates by qRT-PCR and Western Blot analysis to uncover their potential roles in the helper effect, as suggested by their compensatory adjustments in ROS metabolism in this neuroprotective process. In addition a large extant collection of double mutants among genes controlling membrane excitability and metabolic pathways will facilitate construction of an interaction map linking metabolic pathways and neuronal excitability control emanating from Sod function. Missing links and new branches from prominent responder genes may emerge through a microarray analysis. Aim3: The beneficial effects of improved motor coordination and stress resistance will be further correlated with physiological modifications in neurons and neural circuits during aging of Sod flies co-housed with helpers. We will identify resilient physiological parameters as well as labile properties that are prone to Sod mutational perturbations. This will define in concrete physiological terms the landmarks of nervous system aging that are responsive to neuroprotective effect of social interactions.

描述（由申请人提供）：我们发现，在铜/锌超氧化物歧化酶（SOD）缺陷的果蝇 Sod 突变体中，社交互动具有显着、强大的寿命延长效应。缺乏SOD酶活性会阻碍动物清除有氧代谢过程中产生的有害活性氧（ROS）的能力，导致加速衰老和过度应激反应，并与多种神经退行性疾病有关。我们发现，与更年轻或更活跃的果蝇共同饲养时，Sod 突变体不仅表现出双倍的寿命，而且还提高了抗应激能力和运动协调性。这些表型提供了一个敏感系统，用于干预和揭示某些神经保护机制和寿命决定背后的相互作用的遗传网络和代谢途径。我们将采用多学科方法，利用我们实验室和合作者开发的分子、遗传、生理和行为工具来促进相关性在同一个体或同一组果蝇中进行不同水平的研究。目标1：完善行为实验，揭示有益行为互动的本质，以进一步了解草蝇社交互动的神经保护作用。我们的目标是使用我们实验室新开发的自动视频跟踪系统 IowaFLI Tracker 与其他标准行为技术相结合。目标 2：通过 qRT-PCR 和蛋白质印迹分析检查有或没有共养辅助者的草蝇的关键氧化还原酶或其底物，以揭示它们在辅助效应中的潜在作用，正如它们在 ROS 代谢中的补偿性调整所表明的那样神经保护过程。此外，控制膜兴奋性和代谢途径的基因中现存的大量双突变体将有助于构建连接代谢途径和源自Sod功能的神经元兴奋性控制的相互作用图谱。通过微阵列分析可能会出现突出反应基因的缺失链接和新分支。目标 3：改善运动协调性和抗应激能力的有益效果将进一步与与助手共养的草蝇衰老过程中神经元和神经回路的生理变化相关。我们将确定有弹性的生理参数以及容易受到 Sod 突变扰动的不稳定特性。这将以具体的生理学术语定义神经系统衰老的标志，这些标志对社交互动的神经保护作用作出反应。