Regulation of Synaptic Dysfunction and Maintenance with age using Drosophila

使用果蝇调节突触功能和随年龄的维持

• 批准号: 10427175
• 负责人: Daniel T. Babcock
• 金额: $ 33.62万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427175
• 关键词: Address; Adult; Affect; Age; Aging; Amyotrophic Lateral Sclerosis; Behavioral Assay; Biological Assay; Biological Models; Bone Morphogenetic Proteins; Collection; Communication; Complement; Complex; Defect; Denervation; Development; Disease; Drosophila genus; Electrophysiology (science); Event; Functional disorder; Genes; Genetic; Glutamate Receptor; Goals; Golgi Apparatus; Homologous Gene; Human; Immunohistochemistry; Impairment; Maintenance; Measures; Modeling; Molecular; Monitor; Morphology; Motor Neurons; Muscle; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Junction; Pathway interactions; Performance; Physiological; Population; Process; Proteins; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Sorting - Cell Movement; Structure; Synapses; Testing; Time; Transmission Electron Microscopy; age related; design; fighting; fly; functional disability; fused in sarcoma; genome wide screen; genome-wide; in vivo; loss of function; motor neuron degeneration; mutant; nervous system disorder; neuron loss; novel; protein expression; synaptic function; therapeutic target; trafficking; trans-Golgi Network; treatment strategy

Project Summary Although much is known regarding the development of synapses, very little is known about how these complex structures are maintained throughout the aging process. Defects in synaptic communication are responsible for a great number of neurological disorders, and they are associated with the earliest stages of several neurodegenerative diseases. A major hurdle in the field has been the lack of a genetically tractable model system in which to systematically assess synaptic dysfunction over time in vivo. To address this issue, we propose to use Drosophila to examine the structural and functional impairment of synaptic integrity with aging in adult flight muscles. Our guiding hypothesis is that maintaining synaptic structure and function requires a conserved set of genes involved in trans-synaptic signaling, and that disruption of these signaling pathways are among the early deficits in neurological disorders. To test this hypothesis, we propose to pursue three Specific Aims. The first Aim is to identify the mechanisms underlying synaptic dysfunction in mayday mutants, which we previously identified as displaying age-dependent denervation of flight motor neurons. Our second aim is to characterize novel genes associated with synaptic impairment that we identified through a genome-wide screen. Our third Aim is to determine the structural and functional impairment of synapses in a model of Amyotrophic Lateral Sclerosis (ALS). Our proposed research has the potential to reveal the cellular and molecular mechanisms responsible for maintaining synaptic integrity with age, many of which will likely serve as potential therapeutic targets for developing treatment strategies for several neurological disorders.

项目摘要 虽然我们对突触的发育有很多了解，但对这些复杂的突触是如何形成的却知之甚少。 在整个老化过程中保持结构。突触通讯的缺陷 对于大量的神经系统疾病，它们与几个早期阶段有关。 神经退行性疾病该领域的一个主要障碍是缺乏遗传学上易于处理的模型 系统，其中系统地评估体内随时间的突触功能障碍。 为了解决这个问题，我们建议使用果蝇来检查结构和功能 成年飞行肌中突触完整性随年龄增长而受损。我们的指导假设是， 突触结构和功能需要一组保守的基因参与跨突触信号传导， 这些信号通路的中断是神经系统疾病的早期缺陷。为了验证这一 假设，我们提出追求三个具体目标。第一个目标是确定潜在的机制 五月天突变体中的突触功能障碍，我们先前确定为显示年龄依赖性 飞行运动神经元的去神经支配。我们的第二个目标是描述与突触相关的新基因， 我们通过全基因组筛查发现的缺陷。我们的第三个目标是确定结构和 肌萎缩侧索硬化症（ALS）模型中突触的功能损伤。 我们提出的研究有可能揭示细胞和分子机制负责 随着年龄的增长，保持突触的完整性，其中许多将可能作为潜在的治疗目标， 为几种神经系统疾病制定治疗策略。