Dissecting the Roles of Vitamin A in Autoimmunity

项目摘要 已知维生素A及其活性代谢物维甲酸(RA)既有促炎作用，又有促炎作用。 消炎功能取决于不同的环境。RA可以抑制炎症和 在稳定状态下诱导耐受。矛盾的是，它还可以作为佐剂来促进正在进行的 对抗感染的炎症。关于RA功能的这个难题，人们对它的了解要少得多 自身免疫力。关于类风湿关节炎是否以及如何影响其发生和发展尚缺乏证据。 自身免疫性疾病，作为一个整体，它是美国死亡和残疾的主要原因 各州。在拟议的研究中，我们的目标是定义RA在自身免疫中的复杂角色。基座 根据文献和我们的初步结果，我们假设RA对自身免疫的影响 反应依赖于疾病的阶段，而RA抑制了 自身免疫力，但会促进其进展。使用系统性红斑狼疮(狼疮)作为我们的 对于自身免疫疾病模型，我们计划实现两个目的来验证这一假说。目标1是 确定RA是否抑制炎症以防止狼疮的发生，并描绘出 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 这已经开始了，目标2是确定RA促进炎症的机制 自身免疫性狼疮的延续阶段。这项研究的成功完成将阐明 RA在自身免疫中的复杂作用，并提供有关使用或 狼疮患者避免补充维生素A。这样的信息可能有助于减少 这些患者出现和/或严重的炎性症状。

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.