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（由应用程序提供）：唐氏综合症（DS）是智力障碍最常见的遗传形式，每700-1000个活生生中有一个，但目前尚无对这种复杂的神经发育障碍的有效治疗方法。 DS是由21人类染色体的三体性引起的，这导致许多基因过表达。因此，DS治疗中的一个主要障碍是鉴定DS患者新皮层发展的基因的鉴定是有缺陷的，但是潜在的分子和细胞机制知之甚少。长期目标是定义神经元发育的机制，并确定此过程中的缺陷如何导致复杂的脑部疾病。该应用的目的是阐明DS中新皮层中发育缺陷的基础机制。对小鼠的初步研究表明，发生在人类DS患者的大脑中的基因唐氏综合征细胞粘附分子（DSCAM）的过表达导致皮质发育中的缺陷。但是，DSCAM的过表达如何导致皮质发育中的缺陷，或者它是否负责DS中的任何皮质缺陷。解开这些分子和细胞机制将提供有关靶向DSCAM及其信号级联的潜力的见解 DS中的缺陷。提出了以下两个具体目的来解决此问题：1）确定过表达DSCAM会影响皮层发育的信号传导机制； 2）在DS小鼠模型中定义了DSCAM水平增加在皮质发育中的作用。通过使用对DSCAM水平高度敏感的果蝇神经元系统，在阐明DSCAM控制神经元发展的机制方面已取得了相当大的进步。为AIM 1设计的实验将在小鼠新皮层中测试该分子模型。在AIM 2中，将在DS小鼠模式下测试DSCAM及其信号通路对新皮层发育缺陷的贡献。拟议的研究的贡献将是重要的，因为它将阐明与DS相关的皮质发育缺陷背后的分子和细胞机制，并为处理DS中的复杂脑疾病提供潜在的靶标。该应用程序中提出的研究具有创新性，因为它将研究正常和解散的哺乳动物大脑皮质中DSCAM水平增加的作用和潜在机制。它也具有创新性，因为它使用了果蝇系统，该系统对DSCAM水平高度敏感，以识别过表达DSCAM下游的信号传导机制，并结合了果蝇和小鼠系统的强度，以解剖DS中复杂脑疾病的分子和细胞底物。