The metabolic etiology of niacin deficiency

烟酸（维生素B3）是制造烟酰胺腺嘌呤二核苷酸（NAD）所必需的。然后，NAD被用于我们所有的能量产生和分子构建反应中，作为移动电子的一种方式。因此，烟酸缺乏导致健康问题并不奇怪。在人类中，烟酸缺乏会导致糙皮病，这种疾病具有太阳敏感性皮炎和精神分裂症样痴呆的独特症状。有趣的是，参与电子移动反应的其他营养素（核黄素，铁）的缺乏不会导致皮炎或痴呆。ADP-核糖基化反应的发现部分解决了这个难题，它以一种非常不同的方式使用NAD。阳光敏感性表明烟酸在DNA修复过程中的作用，我实验室的大部分工作都集中在NAD作为聚（ADP-核糖）形成的底物上，聚（ADP-核糖）形成是对DNA损伤的反应，是有效DNA修复所必需的。我们已经发现，烟酸缺乏大鼠骨髓细胞中的NAD和聚ADP-核糖水平较低，并且对发展中的白血病敏感。我们认为，大剂量的烟酸将增强癌细胞的凋亡，同时改善正常骨髓细胞的基因组稳定性。烟酸缺乏性痴呆在烟酸治疗后迅速消退，表明NAD参与了神经元信号传导途径。一个可能的机制涉及环ADP-核糖的形成，它控制神经元中的钙水平。我们已经发现，烟酸缺乏的大鼠大脑NAD和环ADP-核糖减少，并且它们改变了空间学习和各种行为测试的变化。大多数形式的学习与突触信号的变化有关，这些变化增加突触强度（长时程增强，LTP）或主动降低突触强度（长时程抑制，LTD）。在未来的工作中，我们将检查海马切片中的LTP和LTD，使用惊吓反射检查与人类痴呆症相关的行为，并检查大脑切片的结构和连接变化。我将继续致力于这些和相关项目，以促进更好地了解烟酸在代谢中的作用以及ADP核糖基化反应在缺乏症病理学中的作用。

Niacin (vitamin B3) is required to make nicotinamide adenine dinucleotide (NAD). NAD is then used in all of our energy producing and molecule building reactions as a way of moving electrons. Thus, it is not surprising that niacin deficiency causes health problems. In humans, niacin deficiency causes the disease pellagra, which has the unique symptoms of sun-sensitive dermatitis and schizophrenia-like dementia. Of interest, deficiencies of other nutrients that participate in electron moving reactions (riboflavin, iron) do not lead to dermatitis or dementia. This puzzle has been partially solved by the discovery of ADP-ribosylation reactions, which use NAD in a very different way. The sun-sensitivity suggests a role for niacin in DNA repair processes, and much of the work in my lab has focused on NAD as a substrate for poly(ADP-ribose) formation, which happens in response to DNA damage and is required for effective DNA repair. We have found that niacin deficient rats have low levels of NAD and poly ADP-ribose in bone marrow cells, and a sensitivity to developing leukemias. We propose that megadoses of niacin will enhance apoptosis in cancer cells, while at the same time improving genomic stability in normal bone marrow cells. The dementia of niacin deficiency resolves rapidly with niacin treatment, suggesting that NAD participates in neuronal signaling pathways. A likely mechanism involves the formation of cyclic ADP-ribose, which controls calcium levels in neurons. We have found that niacin deficient rats have decreases in brain NAD and cyclic ADP-ribose, and they have altered spatial learning and changes in various behavioral tests. Most forms of learning are linked to changes in synaptic signaling that increase synapse strength (long term potentiation, LTP) or activly decrease synaptic strength (long term depression, LTD). In future work, we will examine LTP and LTD in hippocampal slices, use startle reflex to examine behaviours more associated with human dementia, and examine brain sections for structural and connectivity changes. I will continue to work on these and related projects to promote a better understanding of how niacin functions in metabolism and the role of altered ADP-ribosylation reactions in the pathologies of deficiency.