RA通过组蛋白乙酰化调控RORA在孤独症中的作用及机制研究

Autism spectrum disorder (ASD) is one of the world's serious illness disease with the fastest-growing numbers. The pathogenesis of ASD is complex,and its specific causes and risk factors are unclear. So there is no specific treatment for the core symptoms.In recent years, many studies have found the significant correlation between VA and the incidence of ASD. The VA levels of ASD patients are significantly reduced. In addition，many studies have shown that ASD and the regulation of histone acetylation are closely related. RORA is a new candidate gene of ASD, and is directly affected by histone acetylation regulation. Our previous studies found that RA signaling pathway was closely related to the regulation of histone acetylation. The expressions of nuclear retinoic acid receptors (RARs), CBP（a kind of histone deacetylase）were both decreased in the VAD status. And RARα could directly regulate the expression of CBP. All of these suggest that RA may play a protective role in regulating RORA in ASD by regulation of histone acetylation, and which may be the mechanism of VAD affecting the disease process of ASD. Therefore, current project intends to make RA signals and histone acetylation regulation as examples, to further study the specific regulatory mechanisms of VAD in the disease process of ASD. It will help to provide a new theoretical basis and experimental evidence for the prevention and treatment of ASD.

孤独症谱系障碍（ASD）是目前全球患病人数增长最快的严重疾病之一，其发病机制复杂，具体病因及危险因素尚不清楚，因此尚无针对核心症状的特异性治疗。近年来较多研究发现维生素A（VA）与ASD存在显著相关性，ASD病人VA水平显著降低。此外有研究表明ASD与组蛋白乙酰化的调控密切相关，视黄酸核受体相关孤儿受体α（RORA）是一种新的ASD候选基因，其受到组蛋白乙酰化的直接调控；而本课题组前期研究发现RA信号通路与组蛋白乙酰化的调控密切相关，VA缺乏（VAD）时视黄酸核受体RARs与组蛋白乙酰化酶CBP表达均下降，并且RARα可直接调控CBP的表达。提示RA可能通过组蛋白乙酰化调控RORA在ASD中发挥保护作用，VAD可能通过这一机制影响ASD的疾病进程。因此，本项目拟从RA信号与组蛋白乙酰化调控的角度入手，深入探讨VAD在ASD疾病进程中的具体作用机制，为ASD的防治提供新的理论基础和实验依据。

孤独症谱系障碍（ASD）是目前全球患病人数增长最快的严重疾病之一，其发病机制复杂，具体病因及危险因素尚不清楚，因此尚无针对核心症状的特异性治疗。近年来较多研究发现维生素A（VA）与ASD存在显著相关性，ASD病人VA水平显著降低。此外有研究表明ASD与组蛋白乙酰化的调控密切相关，视黄酸核受体相关孤儿受体α（RORA）是一种新的ASD候选基因，其受到组蛋白乙酰化的直接调控；本课题组前期研究发现RA信号通路与组蛋白乙酰化的调控密切相关，VA缺乏（VAD）时视黄酸核受体RARs与组蛋白乙酰化酶CBP表达均下降，并且RARα可直接调控CBP的表达。提示RA可能通过组蛋白乙酰化调控RORA在ASD中发挥保护作用，VAD可能通过这一机制影响ASD的疾病进程。本项目利用ASD及VAD大鼠模型，探讨ASD中RARα信号、CBP依赖的组蛋白乙酰化水平与ASD相关信号分子表达的相关性及VA干预效果；并利用体外小脑组织原代神经元研究进一步揭示RARα、CBP、RORA相互调控的具体分子机制。研究发现ASD及VAD模型大鼠小脑组织中RARα、CBP、RORA表达密切相关，两种模型鼠均出现ASD样行为，而VA补充（VAS）可部分逆转这种行为及相关分子改变。该研究结果从组蛋白乙酰化这一表观遗传的角度阐明VAD在 ASD 疾病进程中的重要作用，进一步的深入探讨将为防治 ASD、提高人口质量提供坚实的理论基础和实验依据。