Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态

• 批准号: 10288703
• 负责人: Joseph A. Baur
• 金额: $ 42.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288703
• 关键词: Administrative Supplement; Affect; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer’s disease biomarker; Animals; Area; Autopsy; Award; Biochemical; Brain; Brain region; Cognition; Cognitive; Cognitive deficits; Data; Disease; Disease Progression; General Population; Genetic; Glutamates; Goals; Grant; Health; Histologic; Human; Imaging Techniques; Individual; Lead; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Metabolism; Mus; Neurons; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Nutraceutical; Obesity; Parents; Pathology; Patients; Rodent; Rodent Model; Sampling; Supplementation; Surgical Models; Synapses; Techniques; Testing; Therapeutic; Time; Translating; United States National Institutes of Health; Vitamins; Work; base; blood glucose regulation; cognitive function; cohort; density; drinking water; early detection biomarkers; experimental study; falls; human subject; improved; innovation; mouse model; nicotinamide-beta-riboside; non-invasive imaging; preservation; response

Abstract In response to NOT-AG-20-034: “Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease”, we propose to take advantage of state-of-the art noninvasive imaging techniques developed at Penn in order to follow changes in brain nicotinamide adenine dinucleotide (NAD) levels over time in the well-characterized 5XFAD mouse model of Alzheimer's disease (AD) with and without a supplemental NAD precursor. These experiments will test whether changes in brain NAD concentration anticipate or correlate with cognitive deficits in live animals. Critically, the MRI-based imaging techniques employed are readily translatable to human subjects. The proposed studies fall within the scope of Aim 2 of the parent award: “Determine the downstream mechanisms that are compromised by NAD limitation and restored by supplemental precursors,” and will add substantial value to the work, as Alzheimer's disease is emerging as a key area in which NAD metabolism may have an impact. Over the past 7 years, multiple studies have demonstrated improvements in cognition in rodent models of AD after supplementing animals with either nicotinamide riboside (NR) or nicotinamide mononucleotide. However, the available data are insufficient to determine conclusively whether supplementation is increasing NAD content in affected brain regions, whether changes in NAD levels precede cognitive effects, or whether they correlate with cognitive function on an individual animal basis. In a few cases, NAD was extracted and measured from post-mortem brain samples, but this is not an ideal approach as it cannot be performed longitudinally, cannot distinguish changes in neuronal NAD concentration from changes in neuronal density, and cannot be used in humans (for obvious reasons in living patients, but also in post- mortem samples, which are almost always collected too slowly to preserve metabolites). MRI solves all of these problems and will allow us to clarify the relevance of NAD metabolism in rodents using a technique that can be readily translated to human patients. In the proposed studies, we will longitudinally follow cognition function and brain NAD levels in cohorts of 5XFAD mice that are untreated or given NR in the drinking water. Brain NAD levels will be overlaid with an MRI-based measure of glutamate concentration (“GluCEST”), which has been recently validated as a marker of synaptic density. At 9 months of age, the cohorts will be sacrificed for histological assessments of AD-related pathology and biochemical determination of metabolite concentrations. These experiments will advance the core goals of the parent award, to understand where and when NAD metabolism is important, and will test a hypothesis that could lead to desperately needed biomarkers for AD, or even a therapeutic approach to delay progression.

摘要 回应NOT-AG-20-034：“针对阿尔茨海默氏症的NIH补助金的行政补充是 不专注于阿尔茨海默病“，我们建议利用最先进的非侵入性成像 宾夕法尼亚大学开发了跟踪大脑烟酰胺腺嘌呤二核苷酸(NAD)变化的技术 阿尔茨海默病(AD)5XFAD小鼠模型中随时间变化的水平 没有补充NAD前体的情况下。这些实验将测试大脑NAD的变化 在活体动物中，注意力可以预测认知缺陷或与之相关。关键是，基于MRI的成像 所使用的技术很容易翻译给人类受试者。拟议的研究属于以下范围 父奖的目标2：“确定受NAD危害的下游机制 限制并通过补充前身恢复“，并将为工作增加实质性价值，如 阿尔茨海默病正在成为NAD代谢可能产生影响的一个关键领域。 在过去的7年里，多项研究表明，啮齿动物模型的认知能力有所改善 在给动物补充烟酰胺核苷(NR)或烟酰胺单核苷酸后。 然而，现有的数据不足以最终确定补充是否 在受影响的大脑区域增加NAD含量，NAD水平的变化是否先于认知效应， 或者它们是否与个体动物的认知功能相关。在少数情况下，NAD是 从死后的大脑样本中提取和测量，但这不是一个理想的方法，因为它不能 纵向执行，不能区分神经元NAD浓度的变化和 神经元密度，不能用于人类(原因很明显，活着的患者，但也在后 身体样本，几乎总是收集得太慢，无法保存代谢物)。核磁共振解决了所有 这些问题，并将使我们能够澄清NAD代谢在啮齿类动物中的相关性 这可以很容易地转化为人类患者。在拟议的研究中，我们将纵向跟踪 5XFAD小鼠中未治疗或给予NR治疗的队列小鼠的认知功能和脑NAD水平 喝水。大脑NAD水平将被基于MRI的谷氨酸浓度测量覆盖 (“GluCEST”)，它最近被证实是突触密度的标志。在9个月大的时候， 将牺牲队列以进行AD相关病理和生化的组织学评估 代谢物浓度的测定。这些实验将推进父母的核心目标 奖，以了解NAD新陈代谢在哪里以及何时是重要的，并将检验一个假设，该假说可能 导致迫切需要的AD生物标志物，甚至是延缓进展的治疗方法。