Mechanisms of White Matter Development in Down Syndrome

项目概要 我们最近对唐氏综合症（DS）患者大脑的转录组分析， 从胎儿期到 40 岁进行的研究，发现了大约 800 项失调 所有染色体上的基因，每个基因都有特定的时间和区域特征。这些 改变的基因形成共表达网络，其中最突出的表明 少突胶质细胞 (OL) 发育和髓鞘形成缺陷。这一发现是一致的 影像学研究表明 DS 患者白质完整性降低。 在 Haydar 和 Gallo 实验室的这项合作研究中，我们将回答关键问题 关于 OL 成熟不良的时间和来源的问题，特别是是否 细胞自主或非细胞自主机制导致细胞改变 分化和髓鞘形成。该项目的目标是从定义 OL发育不良到全面综合的发育时间过程 移植、行为和功能测试以评估其机制 缺陷。这些变化是否可以通过基因剂量标准化或通过 将研究使用新发现的药理学工具促进 OL 成熟 最后一个目标。

PROJECT SUMMARY Our recent transcriptome analysis of the brains of people with Down syndrome (DS), conducted from fetal stages to 40 years old, identified approximately 800 dysregulated genes across all chromosomes, each with specific temporal and regional profiles. These altered genes form co-expression networks, the most prominent of which indicates defective oligodendrocyte (OL) development and myelination. This finding is consistent with imaging studies demonstrating reduced white matter integrity in individuals with DS. In this collaborative study between the Haydar and Gallo labs, we will answer key questions regarding the timing and source of OL dysmaturation, and particularly whether cell-autonomous or non-cell autonomous mechanisms lead to altered cellular differentiation and myelination. The Aims of the project progress from defining the developmental time course of OL dysmaturation to comprehensive and integrated transplantation, behavioral and functional tests to evaluate the mechanism(s) of the defect. Whether these changes can be rescued by gene dosage normalization or by using newly identified pharmacological tools to prompt OL maturation will be studied in the last Aim.