NAD+ and SIRT1 Regulate Mitochondrial Function in Diabetic Neuropathy

NAD 和 SIRT1 调节糖尿病神经病变中的线粒体功能

• 批准号: 9174947
• 负责人: JAMES W RUSSELL
• 金额: $ 41.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174947
• 关键词: Accounting; Affect; Age; Animal Model; Animals; Axon; Bioenergetics; Biology; Biopsy; Cessation of life; Clinical Research; Complex; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Electrophysiology (science); Enzymes; Family; Gender; Goals; High Fat Diet; Human; Investigational Therapies; Knowledge; Life; Manuscripts; Measurement; Metabolic; Metabolism; Methods; Mission; Mitochondria; Molecular; Mus; Natural regeneration; Nerve Fibers; Neurodegenerative Disorders; Neurons; Neuropathy; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Nicotinamide-Nucleotide Adenylyltransferase; Outcome; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathology; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Play; Prevention; Prevention therapy; Preventive; Process; Proteins; Public Health; Regulation; Research; Respiration; Respiratory Chain; Risk Factors; Role; Severities; Signal Pathway; Skin; Spinal Ganglia; Streptozocin; Testing; Therapeutic; Time; Tissues; Transcription Coactivator; United States; United States National Institutes of Health; Up-Regulation; Work; aging gene; axon growth; axon regeneration; base; burden of illness; diabetic; diabetic patient; disability; glycemic control; human subject; improved; knock-down; mitochondrial dysfunction; molecular targeted therapies; neuron loss; neuronal survival; nicotinamide-beta-riboside; novel; novel therapeutics; overexpression; prevent; repaired; respiratory; response biomarker; tool; transcription factor

PROJECT SUMMARY/ABSTRACT The rationale for this proposal is that there is currently no specific medication that prevents or reverses diabetic neuropathy in humans and this is a major gap in scientific knowledge. Oxidative stress and mitochondrial (Mt) dysfunction are recognized as important causative factors in neurodegenerative disease and in diabetic neuropathy. Our central hypothesis is that nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are precursors that in the presence of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) increase tissue NAD+ levels in the peripheral nervous system. This in turn activates SIRT1, and in turn downstream transcription factors, which differentially regulate specific Mt complexes to optimize Mt respiration and prevent Mt degeneration. Our objectives are to determine if NR or NMN can be used as a therapy for experimental diabetic neuropathy, determine if the SIRT1- PGC-1α signaling pathway provides molecular targets for treatment of neuropathy, identify potential Mt respiratory chain targets that may respond to treatment, determine if the axonal enzyme that converts NMN to NAD, Nmnat2, is present in regenerating axons in skin biopsies from diabetic animals and human subjects and if measurement of Nmnat2 may be useful as a marker for response to NR. In the Methods, we will use a variety of molecular, electrophysiology, and pathology tools to achieve the aims of the study. Animal models of type 1 and 2 diabetes will be used to determine the effect of NAD+ and SIRT1 overexpression on neuropathy. In isolated Mt or whole DRG neurons we will manipulate NAD+ and SIRT1 to assess the effect on overall Mt function and specific Mt respiratory complexes. Nmnat2 levels will be determined in control and age and gender matched skin biopsies from subjects with different severity of diabetes and diabetic neuropathy. The preliminary findings support the overall objectives of the proposal and provide promising evidence that NR and NMN would provide a potential therapy for diabetic neuropathy and that NAD+ activation of the SIRT1- PGC-1α signaling pathway is important in regulating Mt respiration. The status of the project based on our recent manuscripts shows that PGC-1α has a key role in regulating Mt function in diabetic neuropathy and that knockdown of PGC-1α intensifies the neuropathy. This novel research will examine the upstream activator of PGC-1α, namely SIRT1 in diabetic neuropathy and help further explore a new potential therapy (NR) that can be taken into clinical studies in a timely manner.

项目总结/摘要 这一建议的理由是，目前没有具体的药物，防止或逆转 糖尿病神经病变的人类，这是一个重大的差距，在科学知识。氧化应激和 线粒体功能障碍是神经退行性疾病的重要致病因素 和糖尿病性神经病变。我们的中心假设是烟酰胺核苷（NR）和烟酰胺 烟酰胺单甘肽（NMN）是在烟酰胺单甘肽存在下 腺苷酸转移酶2（Nmnat 2）增加周围神经系统中组织的NAD+水平。这反过来 激活SIRT 1，进而激活下游转录因子，这些转录因子差异调节特定的Mt 复合物，以优化MT呼吸和防止MT退化。我们的目标是确定NR或 NMN可用于实验性糖尿病神经病变的治疗，确定SIRT 1- PGC-1α 信号通路为神经病变的治疗提供了分子靶点， 可能对治疗有反应的链靶点，确定将NMN转化为NAD的轴突酶， Nmnat 2存在于来自糖尿病动物和人类受试者的皮肤活组织检查中的再生轴突中， Nmnat 2的测量可用作NR应答的标志物。在方法中，我们将使用各种 分子，电生理学和病理学工具，以实现研究的目的。1型动物模型 和2型糖尿病将用于确定NAD+和SIRT 1过表达对神经病变的影响。在 分离的Mt或整个DRG神经元，我们将操纵NAD+和SIRT 1以评估对整体Mt的影响。 功能和特定的MT呼吸复合物。Nmnat 2水平将在对照组和年龄组中测定， 来自患有不同严重程度的糖尿病和糖尿病性神经病变的受试者的性别匹配的皮肤活检。的 初步调查结果支持了该提案的总体目标，并提供了有希望的证据，表明NR 和NMN将为糖尿病神经病变提供潜在的治疗，NAD+激活SIRT 1- PGC-1α信号通路在调节Mt呼吸中起重要作用。该项目的状态基于我们的 最近的手稿表明，PGC-1α在调节糖尿病神经病变的Mt功能中具有关键作用， PGC-1α的敲低使神经病变加重。这项新的研究将检查上游激活剂， PGC-1α，即SIRT 1在糖尿病神经病变中的作用，有助于进一步探索一种新的潜在治疗（NR）， 及时纳入临床研究。