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

项目摘要 烟酰胺腺嘌呤二核苷酸(NAD)是能量必需的酶所必需的氧化还原辅因子。 生产和许多其他细胞过程。NAD还可以作为几个类的共底物 信号转导酶，每一种信号转导酶裂解分子释放烟酰胺。细胞NAD派生出来 来自饮食中的色氨酸(从头合成)、烟酸(Preiss-Handler途径)或从 烟酰胺通过NAD挽救途径。NAD缺乏可由多种细胞因子触发 应激，包括DNA损伤，并被认为在许多代谢， 神经和肌肉疾病：相反，增加NAD+被认为是一种有前途的 治疗策略。在这里，研究人员将合作开发和利用蜂窝高通量 筛选(HTS)试验，以发现和验证增加细胞内NAD+水平的小分子。 这些研究应该发现具有巨大治疗潜力的新的小分子 神经和肌肉，包括脑缺血，沃勒神经变性，错误折叠的普里恩 蛋白质毒性、阿尔茨海默病(AD)、线粒体肌病(MM)、年龄相关性骨骼肌减少和 杜氏肌营养不良症(DMD)。

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).