Mechanisms of White Matter Development in Down Syndrome

项目摘要 我们最近对唐氏综合症（DS）患者的大脑进行了转录组分析， 从胎儿期到40岁，确定了大约800个失调的 所有染色体上的基因，每个都有特定的时间和区域概况。这些 改变的基因形成共表达网络，其中最突出的表明 缺陷的少突胶质细胞（OL）发育和髓鞘形成。这一发现是一致 影像学研究表明DS患者的白色完整性降低。 在海达尔和加洛实验室之间的这项合作研究中，我们将回答关键问题。 关于OL发育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改变的细胞 分化和髓鞘形成。项目的目标从定义 OL发育不良向全面和综合发展的时间进程 移植，行为和功能测试，以评估的机制（S）， 缺损这些变化是否可以通过基因剂量正常化或 将研究使用新发现的药理学工具来促进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.