Administrative Supplement for Research on Vitamin B3 Dietary Supplements for Eye Disease

摘要：维生素B3(烟酰胺)是一种广泛使用的膳食补充剂，通常 作为一种抗衰老剂销售。对维生素B3的科学研究在很大程度上集中在其 作为辅酶和共底物烟酰胺腺嘌呤二核苷酸(NAD+)的前体 这是细胞新陈代谢的关键。NAD+水平的降低被认为与减少 线粒体的效率和促进多种疾病。相反，那些 提高细胞内NAD+水平--如维生素B3饮食补充剂--可能会促进 健康和预防疾病。我们目前提议的研究源于科学工作，这些工作 开始测试这一框架用于治疗失明眼病--青光眼。青光眼是一组 以视网膜神经节细胞(RGC)缺失为特征的年龄相关性神经退行性疾病 和他们的轴突，这通常是由高眼压(IOP)引起的。因为RGC 是有丝分裂后神经元，它们的丧失是永久性的，并导致逐渐衰退，导致 不可逆转的失明。2017年发表在《科学》杂志上的一篇论文表明，与年龄相关的 视网膜中NAD+的减少可能使视网膜神经节细胞易患青光眼，饮食 在一种广泛使用的小鼠模型中补充维生素B3可减轻疾病严重程度 青光眼(DBA/2J模型)。后续研究已经开始测试其他药物，这些药物 调节NAD+，如烟酰胺核苷；用其他形式的 眼科疾病；一些临床试验已经进入第二阶段。尽管取得了这些进展， 关于它的重要性、模型的特殊性以及 这些发现的机制。2019年，我们的青光眼中心启动了一项复制研究 用烟酰胺治疗DBA/2J小鼠，并开始与NEE小鼠模型进行平行研究 严重的先天性青光眼。不幸的是，与新冠肺炎大流行相关的挑战 阻止了我们完成这些实验。本行政副刊适用于 R01EY030366《治疗青光眼的新基因组编辑》，将允许我们 完成对这些小鼠的视神经的定量评估。我们还将检查 饮食中的维生素B3如何改变眼压--这是一个重要但研究不足的问题。具体来说，我们将 测试ATF4激活通路和烟酰胺之间是否存在相互作用。这 补充剂将提高我们的父母奖，并将我们推向改进的青光眼疗法 通过使用定量评估在DBA/2J小鼠身上完成一项重要的复制研究 完成了对患有严重青光眼的NEE小鼠的神经保护测试，以及 测试ATF4和烟酰胺共同影响眼压的机制。

Abstract: Vitamin B3 (nicotinamide) is a widely available dietary supplement that is often marketed as an anti-aging agent. Scientific studies of vitamin B3 have largely centered on its role as a precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme and co-substrate that is key to cellular metabolism. Reductions in NAD+ levels are thought to be linked to reduced mitochondrial efficiency and to promote numerous diseases. Conversely, strategies which increase cellular NAD+ levels―such as vitamin B3 dietary supplementation―might promote health and prevent disease. Our currently proposed studies derive from scientific work that has begun to test this framework for the blinding eye disease, glaucoma. Glaucoma is a group of age-related neurodegenerative diseases characterized by loss of retinal ganglion cells (RGCs) and their axons that is often precipitated by elevated intraocular pressure (IOP). Because RGCs are post-mitotic neurons, their loss is permanent and causes a gradual decline leading toward irreversible blindness. A 2017 paper in the journal Science suggested that an age-related decline of NAD+ in the retina might render RGCs susceptible to glaucoma and that dietary supplementation of vitamin B3 lessened disease severity in one widely used mouse model of glaucoma (the DBA/2J model). Follow-up studies have begun to test additional agents which modulate NAD+, such as nicotinamide riboside; to examine mouse models with other forms of ocular disease; and some clinical trials have advanced to phase 2. Despite these advances, there are many unanswered questions regarding the significance, model specificity, and mechanisms of these findings. In 2019 our Glaucoma Center initiated a replication study of DBA/2J mice treated with nicotinamide and began a parallel study with the nee mouse model of severe congenital glaucoma. Unfortunately, challenges related to the COVID-19 pandemic prevented us from completing these experiments. This administrative supplement for R01EY030366 “Novel Genome Editing for the Treatment of Glaucoma”, will allow us to complete the quantitative assessment of the optic nerves from these mice. We will also examine how dietary vitamin B3 alters IOP―an important but under studied question. Specifically, we will test whether there is an interaction between ATF4 activated pathways and nicotinamide. This supplement will enhance our parent award and move us toward improved glaucoma therapies by completing an important replication study with DBA/2J mice using quantitative assessments of axon number, completing a test of neuroprotection in nee mice with severe glaucoma, and testing a mechanism relevant to both ATF4 and nicotinamide in influencing IOP.