HTS to identify compounds that increase NAD+ levels in neurons and muscle cells

HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物

• 批准号: 10618481
• 负责人: Joseph A. Baur
• 金额: $ 27.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618481
• 关键词: ADME Study; Alzheimer' s Disease; Biological Assay; Biology; Brain Ischemia; Cell Line; Cell physiology; Cells; Cellular Stress; Cessation of life; Chemicals; Collaborations; Collection; Computer Analysis; Consumption; DNA Damage; Dementia; Dermatitis; Development; Diarrhea; Disease; Dose; Drug Kinetics; Duchenne muscular dystrophy; Enzymes; FDA approved; Functional disorder; Genomics; Grant; Hereditary Disease; Homeostasis; Human; In Vitro; Kinetics; Libraries; Link; Luciferases; Mass Spectrum Analysis; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Myopathies; Mus; Muscle; Muscle Cells; Mutation; Myopathy; NADH; Nerve Degeneration; Neurologic; Neuromuscular Diseases; Neurons; Niacinamide; Nicotinamide adenine dinucleotide; Nicotinic Acids; Oxidation-Reduction; Oxides; Pathway interactions; Patients; Pellagra; Permeability; Pharmaceutical Chemistry; Pharmacology; Phase; PrP; Process; Production; Recycling; Reporting; Research Personnel; Rhabdomyosarcoma; Rodent; Secondary to; Signal Transduction; Skeletal Muscle; Solubility; Syndrome; Testing; Therapeutic; Toxic effect; Tryptophan; Unhealthy Diet; Up-Regulation; Validation; age related; assay development; axonal degeneration; base; cheminformatics; cofactor; dietary; enzyme pathway; high throughput screening; in silico; liver metabolism; mdx mouse; mouse model; nervous system disorder; neuromuscular; nicotinamide-beta-riboside; novel; response; sarcopenia; screening; small molecule; small molecule libraries; synergism

Project Summary Nicotinamide adenine dinucleotide (NAD) is a redox cofactor required by enzymes essential to energy production and numerous other cellular processes. NAD also serves as a co-substrate for several classes of signaling enzymes, each of which cleaves the molecule to release nicotinamide. Cellular NAD is derived from dietary tryptophan (de novo synthesis), nicotinic acid (the Preiss-Handler pathway) or recycled from nicotinamide via the NAD salvage pathway. NAD deficiency can be triggered by a variety of cellular stresses, including DNA damage, and is thought to contribute to pathophysiology in a number of metabolic, neurological, and muscular diseases: conversely, increasing NAD+ has been suggested as a promising therapeutic strategy. Here, researchers will collaborate to develop and utilize a cellular High Throughput Screening (HTS) assay to discover and validate small molecules that increase intracellular NAD+ levels. These studies should identify novel small molecules with great therapeutic potential for a myriad of neurological and muscular including brain ischemia, Wallerian nerve degeneration, misfolded prion protein toxicity, Alzheimer's disease (AD), mitochondrial myopathy (MM), age related sarcopenia and Duchenne's muscular dystrophy(DMD).

项目摘要 烟酰胺腺嘌呤二核苷酸（NAD）是酶必需的氧化还原辅因子 生产和许多其他细胞过程。 NAD还用作几个类的共同基底 信号酶的酶，每种酶都裂解了分子以释放烟酰胺。细胞NAD得出 从饮食色氨酸（从头合成），烟酸（预防手柄途径）或从 烟酰胺通过NAD打捞途径。 NAD缺乏症可以由多种细胞触发 压力，包括DNA损伤，被认为在许多代谢中有助于病理生理 神经系统和肌肉疾病：相反，已经提出了增加NAD+作为有希望的 治疗策略。在这里，研究人员将合作开发和利用细胞高通量 筛选（HTS）分析以发现和验证增加细胞内NAD+水平的小分子。 这些研究应鉴定出具有巨大治疗潜力的新型小分子 神经系统和肌肉包括脑缺血，沃勒神经变性，错误折叠的prion 蛋白质毒性，阿尔茨海默氏病（AD），线粒体肌病（MM），与年龄相关的肌肉减少症和 Duchenne的肌肉营养不良（DMD）。