The control of neural transmission by glycosylation

通过糖基化控制神经传递

• 批准号: 8702249
• 负责人: VLADISLAV M PANIN
• 金额: $ 31.05万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702249
• 关键词: Adult; Affect; Animal Model; Area; Arrhythmia; Behavioral; Biochemical; Biological; Biological Models; Biological Process; Biology; Biomedical Research; Brain; Cell Adhesion; Cell Culture Techniques; Cells; Complex; Data; Defect; Development; Disease; Drosophila genus; Electrophysiology (science); Enzymes; Epilepsy; Future; Genes; Genetic; Glycoproteins; Goals; Human; Human body; Individual; Invertebrates; Knowledge; Light; Link; Locomotion; Longevity; Mediating; Microscopy; Molecular; Motor Neurons; Nervous system structure; Neurologic; Neuromuscular Junction; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Organ; Paralysed; Phenotype; Physiology; Play; Polysaccharides; Property; Regulation; Research; Role; Sialic Acids; Sialyltransferases; Specificity; Study models; Synapses; Synaptic Transmission; Techniques; Temperature; Testing; Therapeutic; chronic pain; fly; genetic manipulation; glycosylation; multidisciplinary; nervous system development; nervous system disorder; neural circuit; neurodevelopment; neuroregulation; new technology; novel; novel therapeutics; pleiotropism; protein function; relating to nervous system; research study; sialylation; tool; voltage; voltage gated channel

DESCRIPTION (provided by applicant): Our research focuses on the molecular, cellular, and systemic mechanisms underlying the neural functions of glycoprotein sialylation. Although the brain is the organ with the most prominent sialylation in human body, and recent studies implicated sialylation defects in several neurological diseases, the functions of this important type of glycosylation in the nervous system are still poorly understood. The intricacies of glycosylation, increased pleiotropy and redundancy, and limitations of available genetic approaches significantly hinder the research on sialylation in the overwhelmingly complex vertebrate nervous system. Thus, a suitable model system would be an important tool for more efficient and accelerated studies in this area. Here we propose to use Drosophila as a model organism to investigate the neural functions of N-linked sialylation. We previously characterized Drosophila sialyltransferase, DSiaT, a sole sialyltransferase in Drosophila. This enzyme is highly homologous to its human counterpart which also shares with DSiaT several functional properties, including similar acceptor specificity and an elevated expression in the brain. Our recent experiments revealed that the function of sialylation in Drosophila is limited to the nervous system. We found that sialylation regulates neural transmission and the development of neuromuscular junctions. Abnormal sialylation results in Drosophila in prominent neurological phenotypes, including temperature-sensitive paralysis, defects in locomotion, and a significantly shortened life span. Our experiments indicated that a simple N-linked glycoprotein sialylation plays a prominent role in modulating neural activity, which establishes a new paradigm of the involvement of glycosylation in the nervous system regulation. This novel, nervous system-specific function of N-linked sialylated glycans is potentially conserved between flies and humans. The current project will extend our previous research and will investigate (i) the cellular mechanisms underlying the neural function of sialylation in Drosophila, (ii) the molecular mechanisms of sialylation-mediated control of neural excitability, and (iii) the role of sialylation in neural plasticity. We will use a multidisciplinary strategy, combining the advantages of Drosophila model system, including its exceptional amenability to genetic manipulations, exhaustively characterized neural development, low redundancy and pleiotropy of sialylation genes, with well-established electrophysiological and behavioral approaches, cell culture and biochemical techniques, as well as novel technologies for glycan analyses. This project will shed light on the crucial evolutionarily conserved principles of neural regulation and development, which could be useful for biomedical research and relevant therapeutic strategies. Our research will also establish Drosophila as a versatile model system for future studies of the role of glycosylation in the nervous system.

描述（由申请人提供）：我们的研究重点是糖蛋白溶解酶神经功能的分子，细胞和全身机制。尽管大脑是人体中最突出的溶解作用的器官，并且最近的研究暗示了几种神经系统疾病中的溶缺损，但这种重要类型的神经系统中这种重要类型的糖基化功能仍然很少了解。糖基化的复杂性，多效性增加和冗余的增加以及可用遗传方法的局限性显着阻碍了压倒性复杂的脊椎动物神经系统中溶解的研究。因此，合适的模型系统将是该领域更有效和加速研究的重要工具。在这里，我们建议使用果蝇作为模型生物来研究N连接的溶性的神经功能。我们先前表征了果蝇溶酶体转移酶，dsiat，dsiat是果蝇中的唯一siallyltransferase。该酶与其人类对应物高度同源，该酶也具有多种功能特性，包括类似的受体特异性和大脑中升高的表达。我们最近的实验表明，果蝇中的溶解作用仅限于神经系统。我们发现溶解度调节神经传播和神经肌肉连接的发展。异常的囊化导致果蝇在突出的神经表型中，包括温度敏感性瘫痪，运动缺陷以及显着缩短的寿命。我们的实验表明，简单的N连接糖蛋白溶解酶在调节神经活动中起着重要的作用，该神经活性建立了糖基化参与神经系统调节的新范式。 N-连接的siallated聚糖的新型，神经系统特异性的功能可能在苍蝇和人之间可以保留。当前的项目将扩展我们以前的研究，并将研究（i）果蝇中溶解神经功能的神经功能的基础机制，（ii）（ii）辅助介导的神经兴奋性控制的分子机制，以及（iii）溶解性在神经可塑性中的作用。我们将使用一种多学科策略，将果蝇模型系统的优势结合在一起，包括其对遗传操纵的特殊性，详尽地表征神经发育，低冗余性和siAllation Genes的多效性，以及已建立的电力生理学方法和行为方法和行为方法，细胞培养和生物化学技术，以及Glosical ins Onalliques Gysicies。该项目将阐明神经调节和发展的关键进化保守原则，这对于生物医学研究和相关的治疗策略可能很有用。我们的研究还将建立果蝇作为一种多功能模型系统，用于将来研究糖基化在神经系统中的作用。