Dissecting the Roles of Vitamin A in Autoimmunity

项目摘要 已知维生素A及其活性代谢物视黄酸（RA）发挥促炎和抗炎作用。 抗炎作用取决于不同的环境。RA可以抑制炎症， 在稳定状态下诱导耐受性。巧合的是，它也可以作为一种辅助剂，促进正在进行的 炎症对抗感染。关于RA功能的这个难题， 自身免疫缺乏证据表明RA是否以及如何影响 自身免疫性疾病，作为一个整体是美国死亡和残疾的主要原因， States.在拟议的研究中，我们的目标是确定RA在自身免疫中的复杂作用。基于 根据文献和我们的初步结果，我们假设RA对自身免疫性疾病的影响， 反应取决于疾病的阶段，RA抑制了 自身免疫，但促进其发展。使用系统性红斑狼疮（狼疮）作为我们的 疾病模型的自身免疫性，我们计划实现两个目标来测试这一假设。目标1： 确定RA是否抑制炎症，以防止狼疮的发生，并描绘一个 分子作用机制我们的初步结果表明，类风湿性关节炎会加重狼疮 目的2是确定RA促进炎症的机制， 自身免疫性狼疮的持续期本研究的成功完成将阐明 RA在自身免疫中的复杂作用，并提供关于使用或 避免狼疮患者补充维生素A。这些信息可能有助于减少 这些患者所遭受的炎性发作的发生和/或严重程度。

Project Summary Vitamin A and its active metabolite, retinoic acid (RA), are known to exert both pro-inflammatory and anti-inflammatory functions depending on different contexts. RA can suppress inflammation and induce tolerance under steady state. Paradoxically, it can also act as an adjuvant to promote ongoing inflammation against infections. This conundrum on the functions of RA is much less understood for autoimmunity. Evidence is lacking on whether and how RA affects the initiation and progression of autoimmune disorders, which as a whole are a leading cause of death and disability in the United States. In the proposed research, we aim to define the complex roles of RA in autoimmunity. Based on the literature and our preliminary results, we hypothesize that the effects of RA on autoimmune responses are dependent on the stage of disease and that RA suppresses the initiation of autoimmunity but promotes its progression. Using systemic lupus erythematosus (lupus) as our disease model of autoimmunity, we plan to achieve two aims to test this hypothesis. Aim 1 is to determine whether RA suppresses inflammation to prevent the initiation of lupus and delineate a molecular mechanism of action. As our preliminary results have shown that RA exacerbates lupus that is already initiated, Aim 2 is to determine the mechanism by which RA promotes inflammation in the continuation phase of autoimmune lupus. Successful completion of this study will elucidate the complex roles of RA in autoimmunity and provide much needed information concerning the use of, or avoidance of, vitamin A supplementation in lupus patients. Such information may help decrease the occurrence and/or severity of inflammatory flares suffered by these patients.