Mechanisms of cognitive deficits in dystroglycanopathies

肌营养不良症认知缺陷的机制

基本信息

批准号：
9043921
负责人：
HUAIYU HU
金额：
$ 55.64万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-03 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043921
关键词：
Adult Animal Model Animals Architecture Binding Biochemical Birth Brain Cells Cobblestone Lissencephaly Cognitive Cognitive deficits Cre-LoxP Data Defect Dendritic Spines Development Disease Dystroglycan ECM receptor Electrophysiology (science)Enzymes Extracellular Matrix Family Fukuyama syndrome Genes Goals Health Hippocampus (Brain)Individual Investigational Therapies Knockout Mice Language Lead Learning Learning Disabilities Learning Skill Link Mannose Memory impairment Mental Retardation Methods Mus Mutate Mutation N-Acetylglucosaminyltransferases Neuroglia Neurologic Dysfunctions Neuronal Dysfunction Neuronal Migration Disorder Neurons Neurophysiology - biologic function Outcome Patients Polysaccharides Problem Solving Prosencephalon Proteins Recovery Recovery of Function Role Serotyping Staging Structural defect Structure Synapses Synaptic plasticity Technology Testing Therapeutic Transferase Vertebral column Viral Vector adeno-associated viral vector alpha Dystroglycan base brain dysfunction brain malformation congenital muscular dystrophy density design dystroglycanopathy effective therapy functional improvement functional plasticity gene replacement therapy gene therapy genetic approach glycosylation glycosyltransferase improved interest knockout gene mental function mouse model overexpression postnatal prevent protein expression protein-O-mannosyltransferase 2 reduce symptoms research study restoration skills sugar therapeutic gene

项目摘要

DESCRIPTION (provided by applicant): Dystroglycanopathies are a group of congenital muscular dystrophies that involve brain malformations and severe mental retardation. Most of the identified causes are mutations in glycosyltransferases that cause hypoglycosylation of a-dystroglycan, an extracellular matrix receptor. The brain malformations, including type II lissencephaly are characterized as a type of neuronal migration disorder, for which no effective therapy exists. The long-term goal of this project is to develop gene therapeutic strategies to improve brain function. Surprisingly while abnormal brain architecture is believed to be the most critical contributor to the neural dysfunction and disorders, our recent studies provide compelling evidence that a number of key neural functions depend more critically on ongoing glycosylation in the adult brain. In particular we have found that spatial learning insufficiency is mainly cause by altered dendritic spine plasticity due to defective cell-ECM interactions and that restoration o glycosylation restores spine plasticity and improves brain function despite abnormal histological structures. Therefore, our Hypothesis is that postnatal gene therapy restores spine plasticity and improves brain function despite the malformed brain. This proposal focuses on the mechanisms of spatial learning deficits and its rescue by gene therapy as a first step to improve mental function in dystroglycanopathies. The specific aims are designed to understand the mechanisms of spatial learning deficits and functional recovery by gene therapy. Aim 1: Determine the mechanisms of defective dendritic spine plasticity that contributes to spatial learning deficits in mouse models of dystroglycanopathies. Aim 2: Determine whether restoration of a-dystroglycan glycosylation by gene therapy rescues spatial learning in dystroglycanopathies despite the presence of brain malformations. This proposal will study the basis of spatial learning deficits and their correction via gene therapy without correcting the migration disorder itself using histological, electrophysiological, biochemical, and state-of-the-art genetic approaches. It will lead to improved understanding of the diseases and is expected to produce experimental therapies. The strategy of gene therapy targeted towards postnatal plasticity defects as opposed to correcting developmental histological defects may be broadly useful for other neuronal migration disorders.

描述（通过应用程序提供）：肌性肿瘤疾病是一组先天性肌肉营养不良，涉及大脑畸形和严重的智力低下。大多数确定的原因是糖基转移酶的突变，这些突变引起a-dystroglycan（一种细胞外基质受体）的降糖基化。包括II型Lissencephaly在内的大脑畸形被认为是一种神经元迁移障碍，不存在有效的治疗。该项目的长期目标是制定基因治疗策略来改善大脑功能。令人惊讶的是，虽然脑结构异常被认为是导致神经功能障碍和疾病的最关键的原因，但我们最近的研究提供了引人注目的许多关键神经元功能更严格地取决于成人大脑中持续的糖基化的证据。特别是我们发现，空间学习不足主要是由于细胞ECM相互作用有缺陷引起的树突状脊柱可塑性引起的，并且恢复糖基化恢复了脊柱可塑性并改善了脑功能目的地异常组织学结构。因此，我们的假设是产后基因治疗可恢复脊柱的可塑性并改善大脑的脑功能。该提案的重点是空间学习定义的机制及其基因疗法营救的机制，作为改善多糖肿瘤病理心理功能的第一步。具体目的旨在了解基因治疗的空间学习定义和功能恢复的机制。目的1：确定有缺陷的树突状脊柱可塑性的机制，有助于空间学习定义多糖糖基化的小鼠模型。目标2：确定通过基因疗法恢复A-核糖糖基化糖基化是否是否存在脑畸形，但在多胶糖路径中反应空间学习。该建议将研究空间学习定义的基础及其通过基因疗法进行纠正，而无需使用组织学，电生理学，生化和最先进的遗传方法来纠正迁移障碍本身。这将导致对疾病的了解，并有望产生实验疗法。针对产后可塑性缺陷而不是纠正发展组织学缺陷的基因疗法的策略对于其他神经元迁移障碍可能广泛有用。