Mechanisms underlying defective cortical development in Down syndrome

 描述（申请人提供）：唐氏综合征（DS）是智力残疾的最常见遗传形式，影响每700- 1000个活产婴儿中的一个，但目前没有有效的治疗这种复杂的神经发育障碍。DS是由人类21号染色体的三体性引起的，这导致许多基因的过度表达。因此，DS治疗的一个主要障碍是鉴定作为发病机制驱动因素并可作为有效治疗靶点的基因。DS患者的新皮层发育是有缺陷的，但其潜在的分子和细胞机制尚不清楚。长期目标是确定神经元发育的机制，并确定这一过程中的缺陷如何导致复杂的大脑疾病。本申请的目的是阐明DS中新皮层发育缺陷的分子机制。对小鼠的初步研究表明，唐氏综合征患者大脑中唐氏综合征细胞粘附分子（DSCAM）基因的过度表达会导致皮质发育缺陷。然而，它仍然是未知的DSCAM过度表达如何导致皮质发育的缺陷，或它是否是负责的任何皮质缺陷的DS。解开这些分子和细胞机制将提供深入了解靶向DSCAM及其信号级联的潜力，用于治疗皮质 DS中的缺陷。提出了以下两个具体目标来解决这个问题：1）确定过表达的DSCAM影响皮质发育的信号传导机制;和2）定义DS小鼠模型中增加的DSCAM水平在皮质发育中的作用。通过使用果蝇神经元系统的发展是高度敏感的DSCAM水平，在阐明DSCAM控制神经元发育的机制已经取得了相当大的进展。为目标1设计的实验将在小鼠新皮层中测试这种分子模型。在目的2中，将在DS小鼠模式中测试DSCAM及其信号传导途径对新皮质中发育缺陷的贡献。拟议的研究的贡献将是显着的，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，并提供潜在的目标，治疗复杂的大脑疾病的DS。本申请中提出的研究是创新的，因为它将研究正常和患病哺乳动物大脑皮质中DSCAM水平增加的作用和潜在机制。它也是创新的，因为它使用了一个果蝇系统，是高度敏感的DSCAM水平，以确定下游的信号转导机制过表达的DSCAM和结合的力量，果蝇和小鼠系统在解剖复杂的大脑疾病的分子和细胞底物的DS。

 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.