Mechanisms underlying defective cortical development in Down syndrome

唐氏综合症皮质发育缺陷的机制

• 批准号: 9111290
• 负责人: BING YE
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111290
• 关键词: Address; Affect; Brain; Brain Diseases; Cell Adhesion Molecules; Chromosomes, Human, Pair 21; Complex; Defect; Development; Down Syndrome; Down Syndrome Cell Adhesion Molecule; Drosophila genus; Exhibits; Gene Dosage; Genes; Genetic; Goals; Human; Human Chromosomes; Immigration; Intellectual functioning disability; Knowledge; Lead; Live Birth; Mental disorders; Mission; Molecular; Molecular Models; Mus; Neocortex; Neurodevelopmental Disorder; Neurons; Organism; Pathogenesis; Patients; Phosphotransferases; Process; Protein Tyrosine Kinase; Proteins; Radial; Research; Role; Signal Pathway; Signal Transduction; System; Testing; Trisomy; base; design; effective therapy; innovation; insight; migration; molecular modeling; mouse Ts65Dn; mouse model; neocortical; nervous system disorder; neuron development; overexpression; public health relevance; research study

 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.

 描述（由申请人提供）：唐氏综合症（DS）是最常见的智力障碍遗传形式，每 700-1000 名活产婴儿中就有一人患有唐氏综合症，但目前尚无针对这种由唐氏综合症引起的复杂神经发育障碍的有效治疗方法。人类 21 号染色体三体性，导致许多基因过度表达。因此，DS 治疗的一个主要障碍是识别作为发病机制驱动因素的基因，并可以针对这些基因进行有效治疗。 DS 患者的新皮质发育存在缺陷，但对其潜在的分子和细胞机制知之甚少。长期目标是确定神经发育的潜在机制，并确定该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 新皮质发育缺陷的分子机制。对小鼠的初步研究表明，人类 DS 大脑中存在唐氏综合症细胞粘附分子 (DSCAM) 基因的过度表达。然而，目前尚不清楚 DSCAM 过度表达如何导致皮质发育缺陷，或者它是否与 DS 中的任何皮质缺陷有关。解开这些分子和细胞机制将有助于深入了解 DS 的潜力。靶向 DSCAM 及其信号级联用于治疗皮质 提出以下两个具体目标来解决这个问题：1）确定过度表达的 DSCAM 影响皮质发育的信号机制；2）定义 DS 小鼠模型中 DSCAM 水平增加在皮质发育中的作用。利用其发育对 DSCAM 水平高度敏感的果蝇神经系统，在阐明 DSCAM 控制神经发育的机制方面取得了相当大的进展。为目标 1 设计的实验将测试该分子模型。在目标 2 中，DSCAM 及其信号通路对新皮质发育缺陷的影响将在 DS 小鼠模式中进行测试。所提出的研究的贡献将是重大的，因为它将阐明潜在的分子和细胞机制。与 DS 相关的皮质发育缺陷，并为治疗 DS 复杂脑部疾病提供潜在靶标。本申请中提出的研究具有创新性，因为它将研究正常和正常皮质中 DSCAM 水平增加的作用和潜在机制。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，并结合果蝇和小鼠系统的优势来剖析复杂脑部疾病的分子和细胞基质。在 DS 中。