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）是能量必需酶所需的氧化还原辅因子 生产和许多其他细胞过程。NAD还充当几种类别的共底物 每一种酶都能切割分子释放烟酰胺。细胞NAD衍生 从饮食中的色氨酸（从头合成），烟酸（Preiss-peptide途径）或从 烟酰胺通过NAD补救途径。NAD缺乏可由多种细胞因子引起。 压力，包括DNA损伤，并被认为有助于在一些代谢， 神经和肌肉疾病：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一种细胞高通量 筛选（HTS）试验，以发现和验证增加细胞内NAD+水平的小分子。 这些研究应该确定新的小分子，具有巨大的治疗潜力，为无数的 神经和肌肉，包括脑缺血、沃勒神经变性、错误折叠的朊病毒 蛋白质毒性、阿尔茨海默病（AD）、线粒体肌病（MM）、年龄相关的肌肉减少症和 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).