MECP2倍增大鼠自闭症模型全脑结构和功能病变的多模态磁共振影像研究和针对性基因治疗

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders defined by abnormal behaviors and remains lack of reliable biological markers. Magnetic resonance imaging（MRI）have widely been applied to study brain abnormalities of ASD, and have shown to be potential for earlier diagnosis than behavioral examinations. Due to the limitations of clinical study, there are several crucial issues needed to be resolved with the assistance of animal model, such as the effects of mutations of specific ASD-related gene on brain, the underlying neuropathology of MRI phenotype, and the exploration of therapeutic schedule. MECP2 is a critical gene for neurodevelopmental regulation, duplication of which would lead to ASD. We will investigate brain-wide structural and functional alterations resulting from MECP2 overexpression based on MECP2 duplication model of ASD with multi-modal MRI techniques. By combining behavioral tests, electrophysiological recordings and histological examinations, we will relate the observed MRI phenotype with ASD-like behaviors and underlying neuropathology. On this basis, we will further recover the normal MECP2 expressing level of specific brain areas via targeted virus to explore the possibility of targeted gene therapy. We hope this project will advance our understanding on the MECP2 duplication caused and ASD behaviors related brain abnormalities, and provide feasible suggestion on clinical targeted gene therapy.

自闭症谱系障碍（Autism Spectrum Disorder，ASD）是一类靠行为异常定义的神经发育疾病，仍缺乏可靠生物标志物。磁共振成像被广泛用于ASD脑异常研究，并展示出早于行为标准进行诊断的潜力。由于临床研究的局限，一些重要问题需要结合动物模型来解决，如：特定ASD相关基因的突变对大脑的影响、影像表型的神经病理基础和探索治疗方案。MECP2是神经发育调控的关键基因，倍增会导致ASD。本项目拟基于MECP2倍增大鼠ASD模型，使用多模态磁共振成像研究MECP2过表达对全脑结构与功能的影响。并结合行为测试、电生理记录和组织化学技术，建立影像表型与ASD样行为和神经病理之间的联系。基于此，本项目将进一步使用针对性病毒恢复特定脑区的MECP2表达水平，探索针对性基因治疗的可能性。本项目将促进对MECP2倍增引起的、与ASD行为相关的大脑异常的认识，对临床针对性基因治疗的可行性提供参考。

自闭症谱系障碍(Autism Spectrum Disorder，ASD)是一类靠行为异常定义的神经发育疾病，仍缺乏可靠生物标志物。磁共振成像被广泛用于ASD脑异常研究，并展示出早于行为标准进行诊断的潜力。由于临床研究的局限，一些重要问题需要结合动物模型来解决，如:特定ASD相关基因的突变对大脑的影响、影像表型的神经病理基础和探索治疗方案。MECP2是神经发育调控的关键基因，倍增会导致ASD。本项目基于MECP2倍增大鼠ASD模型，开展多模态磁共振影像研究，并结合行为学实验，建立了磁共振影像特征改变与自闭症样的行为关系，主要发现内侧前额叶皮层的局部功能连接和低频振幅分数均降低，且与ASD样行为相关。跨物种多模态数据融合分析发现，ASD患者内侧前额叶皮层的低频振幅分数也降低，且与ASD行为相关。此外也发现MECP2倍增鼠的海马区域的灰质体积增高，但是跨物种多模态数据融合分析没有发现ASD患者存在类似的改变。通过针对性地恢复内侧前额叶MECP2的表达水平，确实能够逆转动物模型自闭症样行为。本项目的结果表明，内侧前额叶可能是MECP2倍增导致的ASD的关键靶点。

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