维生素A及其核受体在孤独症谱系障碍发病机制中的作用

ASD (autism spectrum disorder) is currently one of the world's serious illness diseases with the fastest-growing numbers and the most common causes of disability in children. The pathogenesis of ASD is very complex and the specific cause is not clear. There is a big challenge for the early diagnosis. Currently there is no exact treatment for the core symptoms of ASD. International studies suggest that vitamin A may be involved in the pathogenesis of ASD. And international studies and our previous studies have suggested that children with ASD are seriously lack of dietary VA (vitamin A). Our study team have found that ASD children are with significantly lower serum VA, and the RARs (retinoic acid receptors)(RARα, RARγ) expressions in the white blood cells of children with ASD decrease significantly; Numerous studies confirm that there is a close relationship between ASD-related symptoms and CD38, OXT, RORA expressions, and CD38, OXT, RORA expressions are closely correlated with VA and RARs. All of these suggest that VA possibly regulate CD38, OXT and RORA expressions through RARs, increasing the risk of ASD in VAD (vitamin A deficiency) condition. Therefore, based on our preliminary work, this study is intended to have a further study on the roles of VA and RARs in the pathogenesis of ASD, and expect to provide important theoretical and experimental basis for the early diagnosis and intervention of ASD.

孤独症谱系障碍(Autism spectrum disorder，ASD)是目前全球患病人数增长最快的严重疾病和导致儿童残障最常见的原因之一。ASD发病机制非常复杂、具体病因尚不清楚，早期诊断存在很大挑战，目前尚无针对ASD核心症状的确切疗法。国际研究提示维生素A(VA)可能参与ASD发病，国内外及本课题组前期研究提示ASD膳食VA存在严重缺乏，本课题组发现ASD儿童血清VA显著降低、血白细胞视黄酸核受体RARs（RARα、RARγ）表达显著下降；大量研究证实ASD相关症状与CD38、OXT、RORA存在密切关系，而CD38、OXT、RORA与VA及RARs紧密联系，提示VA可能通过RARs调节CD38、OXT及RORA的表达，增加VAD时ASD的发病风险。为此，本课题拟以前期工作为基础，深入研究VA及RARs在ASD发病机制中的作用，期望为ASD的早期诊断和干预提供重要的理论和实验依据。

孤独症谱系障碍（ASD）是一种全球患病人数增长最快复杂的神经发育障碍疾病，目前病因不清，早期识别和干预可明显提高预后。维生素A（VA）缺乏是全球发展中国家公共卫生问题，近年发现与脑发育密切相关。本课题第一是通过重庆、海南、西安三地建立ASD与对照儿童队列研究，发现ASD儿童身高体重明显低于对照组，前三位缺乏微量营养素依次为VA、VD和铁；ASD外周血VA水平与社交量表SRS、CARS分呈显著负相关，提示VA水平越低，ASD儿童社交功能越差，外周血OXT水平与SRS量表分呈显著负相关，提示OXT水平越低，ASD儿童社交功能越差 ，ASD儿童外周血VA水平与OXT呈正相关趋势，提示VA可能是增加ASD发病的重要因素。第二是不仅观察了ASD儿童VA大剂量干预后临床和分子变化，揭示VAD增加ASD发病风险的因果关系，且首次探讨了采用每日营养素可耐受摄入量（UL）补充可更好改善ASD儿童社交能力，而WHO推荐用于普通VAD儿童每半年一次20万大剂量补充方法只能维持VA在低水平不下降，而用UL方案口服补充方案后，ASD儿童社交功能恢复更好，但需要进一步扩大样本量验证。VA补充后OXT、OXTR基因有显著上升， RARb上升明显，提示RARb可能对OXT、OXTR基因有调控作用。第三是通过体外ASD儿童外周血淋巴细胞培养、大鼠原代神经元培养研究，抑制或过表达RARs，进一步揭示VA及其信号通路对CD38、OXT、RORA表达调控的具体分子机制。第四是拓展研究首次发现VA和VD联合缺乏加重ASD症状；2.补充VA还可能通过调节5-HT和肠道菌群有益于ASD康复；3.MRI检测ASD儿童大脑特殊部位结构与功能发育不相称可望作为ASD早期诊断的生物标志，正在继续研究；4.还首次发现VA与ASD共病肠道问题发生密切相关，VAD可能通过影响肠道神经发育而引起肠道问题。经过4年的研究，目前远超出所设定的目标，发现VA与ASD儿童社交能力密切关联，有望成为ASD亚型分类的重要参考指标和康复的辅助手段，目前正在通过全国14省多中心研究验证这些结果，期望为孕期预防ASD和临床分型提供重要线索。

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