Mechanisms underlying defective cortical development in Down syndrome

 描述(申请人提供)：唐氏综合症(DS)是最常见的智力残疾的遗传形式，每700-1000名活产中就有一名受到影响，但目前还没有有效的治疗方法来治疗这种复杂的神经发育障碍。DS是由人类21号染色体的三体引起的，这导致了许多基因的过度表达。因此，DS治疗的一个主要障碍是确定哪些基因是致病机制的驱动因素，并可以作为有效治疗的靶点。DS患者的新皮质发育有缺陷，但其潜在的分子和细胞机制尚不清楚。长期目标是定义神经元发育的潜在机制，并确定这一过程中的缺陷如何导致复杂的大脑疾病。这项应用的目的是阐明DS患者新皮质发育缺陷的分子机制。对小鼠的初步研究表明，唐氏综合症细胞黏附分子(DSCAM)基因的过度表达，发生在人类DS患者的大脑中，导致皮质发育缺陷。然而，目前尚不清楚DSCAM过度表达是如何导致皮质发育缺陷的，也不知道它是否与DS的任何皮质缺陷有关。解开这些分子和细胞机制将提供对靶向DSCAM的潜力及其治疗皮质的信号级联的洞察。 DS中的缺陷。为了解决这一问题，我们提出了以下两个具体目标：1)确定过表达的DSCAM影响皮质发育的信号机制；2)在DS小鼠模型中确定DSCAM水平升高在皮质发育中的作用。通过利用对DSCAM水平高度敏感的果蝇神经系统，在阐明DSCAM控制神经元发育的机制方面已经取得了相当大的进展。为Aim 1设计的实验将在小鼠新皮质中测试这个分子模型。在目标2中，将在DS小鼠模型中检测DSCAM及其信号通路在新皮质发育缺陷中的作用。这项拟议的研究将做出重大贡献，因为它将阐明与DS相关的皮质发育缺陷的分子和细胞机制，并为治疗DS的复杂脑部疾病提供潜在的靶点。这项申请中提出的研究具有创新性，因为它将研究正常和疾病哺乳动物大脑皮质中DSCAM水平升高的作用和潜在机制。它还具有创新性，因为它使用对DSCAM水平高度敏感的果蝇系统来识别过度表达的DSCAM下游的信号机制，并结合了果蝇和小鼠系统在解剖DS复杂脑部疾病的分子和细胞底物方面的优势。

 DESCRIPTION (provided by applicant): Down syndrome (DS) is the most common genetic form of intellectual disability, affecting one in every 700- 1000 live births, but there is currenty no effective treatment for this complex neurodevelopmental disorder. DS is caused by the trisomy of human chromosome 21, which leads to overexpression of a number of genes. In consequence, a major hurdle in DS treatment is the identification of genes that are the drivers of pathogenesis and can be targeted for effective therapies. The development of the neocortex of DS patient is defective, but the underlying molecular and cellular mechanisms are poorly understood. The long-term goal is to define the mechanisms underlying neuronal development and to determine how defects in this process lead to complex brain disorders. The objective of this application is to elucidate the molecular mechanism underlying the developmental defects in the neocortex in DS. The preliminary studies in mice suggest that overexpression of the gene Down syndrome cell adhesion molecule (DSCAM), which occurs in the brains of human DS patients, leads to defects in cortical development. However, it remains unknown how DSCAM overexpression causes defects in cortical development, or whether it is responsible for any of the cortical defects in DS. Unraveling these molecular and cellular mechanisms will provide insights into the potential of targeting DSCAM and its signaling cascades for treating the cortical defects in DS. The following two specific aims are proposed to address this issue: 1) identify the signaling mechanism by which overexpressed DSCAM affects cortical development; and 2) define the role of increased DSCAM levels in cortical development in a DS mouse model. By using a Drosophila neuronal system whose development is highly sensitive to DSCAM levels, considerable progress has been made in elucidating the mechanism by which DSCAM controls neuronal development. Experiments designed for Aim 1 will test this molecular model in mouse neocortex. In Aim 2, the contribution of DSCAM and its signaling pathway to the developmental defects in neocortex will be tested in a DS mouse mode. The contribution of the proposed research will be significant because it will elucidate the molecular and cellular mechanisms underlying the cortical developmental defects associated with DS and to provide potential targets for treating the complex brain disorder in DS. The research proposed in this application is innovative because it will investigate the roles and the underlying mechanisms of increased DSCAM levels in the cortices of normal and diseased mammalian brains. It is also innovative because it uses a Drosophila system that is highly sensitive to DSCAM levels to identify signaling mechanisms downstream of overexpressed DSCAM and combines the strength of Drosophila and mouse systems in dissecting the molecular and cellular substrates of the complex brain disorders in DS.