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: 10665088
• 负责人: Joseph A. Baur
• 金额: $ 37.32万
• 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/10665088
• 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; Pathway interactions; Patients; Pellagra; Permeability; Pharmaceutical Chemistry; Phase; PrP; Process; Production; Recycling; Reporting; Research Personnel; Rhabdomyosarcoma; Rodent; Secondary to; Signal Transduction; Skeletal Muscle; Solubility; Sorting; Source; Syndrome; Testing; Therapeutic; Toxic effect; Tryptophan; Unhealthy Diet; Up-Regulation; Validation; age related; assay development; axonal degeneration; cheminformatics; cofactor; counterscreen; dietary; enzyme pathway; high throughput screening; in silico; liver metabolism; mdx mouse; mouse model; nervous system disorder; neuromuscular; nicotinamide-beta-riboside; novel; pharmacologic; 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).

项目概要 烟酰胺腺嘌呤二核苷酸 (NAD) 是能量必需酶所需的氧化还原辅因子 生产和许多其他细胞过程。 NAD 还可以作为多个类别的共同底物 信号酶，每种酶都会裂解分子以释放烟酰胺。细胞NAD衍生 来自膳食色氨酸（从头合成）、烟酸（Preiss-Handler 途径）或回收自 烟酰胺通过 NAD 补救途径。 NAD缺乏可由多种细胞引发 压力，包括 DNA 损伤，被认为有助于许多代谢、 神经系统和肌肉疾病：相反，增加 NAD+ 被认为是一种有希望的治疗方法 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) 测定法可发现和验证可增加细胞内 NAD+ 水平的小分子。 这些研究应该鉴定出对多种疾病具有巨大治疗潜力的新型小分子。 神经和肌肉疾病，包括脑缺血、沃勒神经变性、错误折叠朊病毒 蛋白质毒性、阿尔茨海默病 (AD)、线粒体肌病 (MM)、年龄相关性肌少症和 杜氏肌营养不良症（DMD）。