OGlcNAc as a regulator of mitochondrial motility in diabetic neuropathy

OGlcNAc 作为糖尿病神经病变线粒体运动的调节剂

• 批准号: 8590809
• 负责人: Cathy Su
• 金额: $ 3.41万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590809
• 关键词: Acute; Adaptor Signaling Protein; Address; Affect; Animal Model; Axon; Behavioral; Bioenergetics; Carrier Proteins; Cell Culture Techniques; Cell physiology; Cells; Chronic; Complications of Diabetes Mellitus; Detection; Diabetic Neuropathies; Diabetic mouse; Enzymes; Exhibits; Glucose; Goals; Health; Hexosamines; Hippocampus (Brain); Homeostasis; Hyperglycemia; In Vitro; Mediator of activation protein; Membrane Potentials; Metabolic; Mitochondria; Modification; Morphology; Mus; Mutate; Neurodegenerative Disorders; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; O-GlcNAc transferase; Pathogenesis; Pathway interactions; Peripheral; Physiological; Post-Translational Protein Processing; Production; Proteins; Reactive Oxygen Species; Regulation; Relative (related person); Role; Site; Spinal Ganglia; Stress; Testing; Western Blotting; Work; afferent nerve; base; cell motility; glycosylation; improved; in vivo; insight; interest; mitochondrial membrane; mouse model; novel; public health relevance; research study; sensor; trafficking; trait

DESCRIPTION (provided by applicant): The regulation of mitochondrial transport in neurons is of particular interest due to the unique morphology of neurons and their high energy demands. Defective mitochondrial trafficking can induce changes in mitochondrial fusion/fission dynamics, local bioenergetic profiles, reactive oxygen species (ROS) production, and Ca2+ homeostasis. Several studies have associated altered mitochondrial transport with axon degeneration and the pathogenesis of neurodegenerative disorders, thus demonstrating the importance of the regulation of mitochondrial transport. Previously, the mitochondrial transport adaptor protein, Milton, was shown to interact with O-GlcNAc transferase, the enzyme that catalyzes the addition of O- GlcNAc to proteins. O-GlcNAc is a dynamic post-translational modification that modulates a wide variety of cellular processes and is thought to be a metabolic sensor. Recent work in the Schwarz lab demonstrated that acute changes in glucose levels can regulate mitochondrial trafficking in neurons through the O-GlcNAcylation of Milton1. This leads to the question of whether altered O-GlcNAc dynamics in neurons under chronic hyperglycemic conditions is involved in the pathogenesis of diabetic neuropathy, and in particular whether dysregulation of mitochondrial transport is a contributing factor. The goals of this proposal are: 1. To investigate changes in the O-GlcNAc levels of Milton1 in hyperglycemic neurons. 2. To associate changes in mitochondrial and axonal health with changes in mitochondrial motility 3. To determine the physiological relevance of Milton1 O-GlcNAcylation in vivo. 4. To determine the role of O- GlcNAcylation of Milton1 in mouse models of diabetic neuropathy. By addressing these questions, this proposal aims to further elucidate the significance of dynamic O-GlcNAc levels and the regulation of mitochondrial motility in mammalian neurons under conditions of hyperglycemia and diabetic neuropathy. Overall, the completion of the proposal will provide broad insight on the role of mitochondria in axon degeneration and neuropathy as well as further characterization of a novel regulatory role of the O-GlcNAc modification.

描述（由申请人提供）：由于神经元的独特形态及其高能量需求，神经元中线粒体转运的调节特别感兴趣。线粒体运输有缺陷会诱导线粒体融合/裂变动力学，局部生物能曲线，活性氧（ROS）产生（ROS）和Ca2+稳态的变化。几项研究已将线粒体转运与轴突变性和神经退行性疾病的发病机理相关联，从而证明了线粒体转运的调节的重要性。以前，线粒体转运衔接蛋白米尔顿（Milton）被证明与O-GlCNAC转移酶相互作用，O-GLCNAC转移酶是催化o-GlcNAC添加到蛋白质中的酶。 O-GLCNAC是一种动态的翻译后修饰，可调节多种细胞过程，被认为是代谢传感器。 Schwarz实验室的最新工作表明，葡萄糖水平的急性变化可以通过Milton1的O-Glcnacylation调节神经元的线粒体贩运。这导致了一个问题，即在慢性高血糖状况下神经元中神经元中的O-GLCNAC动力学是否参与糖尿病神经病的发病机理，特别是线粒体转运的失调是否是促成因素。该提案的目标是：1。研究高血糖神经元中MILTON1 O-GLCNAC水平的变化。 2。将线粒体和轴突健康的变化与线粒体运动的变化相关联3。确定体内Milton1 O-Glcnacylation的生理相关性。 4。确定米尔顿1在糖尿病神经病小鼠模型中的o- glcnacylation的作用。通过解决这些问题，该提案旨在进一步阐明动态O-GLCNAC水平的重要性以及在高血糖和糖尿病神经病条件下哺乳动物神经元中线粒体运动的调节。总体而言，该提案的完成将为线粒体在轴突变性和神经病中的作用提供广泛的见解，并进一步表征O-GLCNAC修饰的新调节作用。