The role of sialylation in glia-neuron communications and stress responses

唾液酸化在胶质神经元通讯和应激反应中的作用

• 批准号: 10928423
• 负责人: VLADISLAV M PANIN
• 金额: $ 36.44万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10928423
• 关键词: Acceleration; Affect; Aging; Area; Biochemical; Biological Models; Biology; Biomedical Research; Brain; Cells; Cellular Stress; Chemicals; Chemistry; Communication; Complex; Confocal Microscopy; Coupling; Cytidine Monophosphate N-Acetylneuraminic Acid; Data; Defect; Development; Disease; Drosophila genus; Enzymes; Genes; Genetic; Glycoproteins; Goals; Golgi Apparatus; Heat Stress Disorders; Homeostasis; Human; Human body; In Vitro; Ligase; Link; Mammals; Mediating; Methods; Modeling; Molecular; Molecular Genetics; Molecular Target; Nerve Degeneration; Nervous System; Neurobiology; Neuroglia; Neuromuscular Junction; Neurons; Neurophysiology - biologic function; Organ; Oxidative Stress; Pathologic; Pathway interactions; Physiology; Play; Process; Protein Glycosylation; Regulation; Research; Resistance; Role; Sialyltransferases; Sodium Channel; Stress; Study models; Testing; biological adaptation to stress; genetic approach; genetic manipulation; glycoproteomics; glycosylation; in vivo; insight; model organism; nervous system disorder; neural; neurodevelopment; neurological pathology; neuroregulation; novel; novel therapeutic intervention; pleiotropism; protein function; sialylation; stress tolerance; sugar; tool; voltage; voltage gated channel

The project focuses on the molecular, cellular, and genetic 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. A suitable model system would be an important tool for more efficient mechanistic studies in this area. The proposal focuses on Drosophila as a model organism to investigate the neural functions of N-linked sialylation. Several key evolutionarily conserved enzymes were previously characterized in the Drosophila sialylation pathway, including DSiaT, a sole sialyltransferase in Drosophila, and CSAS, CMP-Sialic Acid Synthetase producing sugar donor for DSiaT. Using a combination of in vitro and in vivo approaches, previous studies revealed that Drosophila sialylation is highly regulated process limited to the nervous system and involved in control of neural excitability, development of neuromuscular junctions (NMJs), and the regulation of voltage-gated channels. Novel functions of N-linked sialylation in the nervous system regulation suggested by previous research are expected to be conserved in humans and be relevant for pathologic mechanisms of neurological diseases. Preliminary research revealed that sialylation is involved in glia-neuron interactions, and that defects of sialylation result in neurodegeneration and increased sensitivity to oxidative stress. CSAS was found to be responsible for rate-limiting effect on Drosophila sialylation, playing a key role in neural regulation. The proposed project will capitalize on previous and preliminary data to extend research towards (i) revealing sialylation-mediated mechanisms of glia-neuron coupling, (ii) elucidating the role of sialylation in promoting neuronal viability and resistance to oxidative stress, (iii) characterizing functional and molecular targets of sialylation using advanced chemical biology and glycoproteomics approaches. The research plan is based on interdisciplinary strategy that combines the advantages of Drosophila model, including amenability to genetic manipulations, exhaustively characterized nervous system, low redundancy of glycosylation pathways, and well-established neurobiological methods, with advanced biochemical and glycoproteomic approaches. The results will shed light on conserved principles of neural regulation and homeostasis, which will be valuable for biomedical feilds. Moreover, the project will establish Drosophila as a versatile model for future research on glycosylation in the nervous system to uncover pathological mechanisms of neurological diseases.

该项目重点研究神经功能潜在的分子、细胞和遗传机制。 糖蛋白唾液酸化。虽然大脑是人体中唾液酸化最突出的器官，但 最近的研究表明唾液酸化缺陷与几种神经系统疾病有关，这一重要类型的功能 神经系统中的糖基化作用仍然知之甚少。糖基化的错综复杂，增加 多效性和冗余性，以及现有遗传方法的局限性，大大阻碍了对 在极其复杂的脊椎动物神经系统中的唾液酸化。一个合适的模型系统应该是 这是在这一领域进行更有效的机制研究的重要工具。该提案的重点是以果蝇为模型 研究N-连结唾液酸化的神经功能。进化上保守的几个关键 此前，果蝇唾液酸化途径中的酶的特征包括DSiaT，一种唯一的 果蝇的唾液酸转移酶，以及DSiaT的CSAS，CMP-唾液酸合成酶产糖供体。vbl.使用 结合体外和体内的方法，以前的研究表明，果蝇唾液酸化是高度 仅限于神经系统并参与控制神经兴奋性的调节过程，发育 神经肌肉接头(NMJ)和电压门控通道的调节。N-链的新功能 以前的研究表明，神经系统调节中的唾液酸化有望在 并与神经系统疾病的病理机制有关。初步研究显示， 唾液酸化参与了胶质细胞-神经元相互作用，唾液酸化缺陷会导致神经变性和 对氧化应激的敏感度增加。研究发现，CSA对果蝇具有限速作用 唾液酸化在神经调节中起着关键作用。拟议的项目将利用以前和初步的经验。 将研究扩展到(I)揭示唾液酸化介导的神经胶质细胞-神经元偶联的机制，(Ii) 阐明唾液酸化在促进神经元活性和抗氧化应激中的作用，(Iii) 用先进的化学生物学和分子生物学表征唾液酸化的功能和分子靶点 糖蛋白组学方法。研究计划基于跨学科战略，结合了 果蝇模型的优点，包括对遗传操作的适应性，详尽地描述了 神经系统，糖基化途径的低冗余性，以及成熟的神经生物学方法， 先进的生化和糖蛋白组学方法。这一结果将阐明守恒原则 神经调节和动态平衡，这对生物医学领域将是有价值的。此外，该项目将 建立果蝇作为未来神经系统糖基化研究的通用模型 神经系统疾病的病理机制。