权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8864786
负责人：
HUAIYU HU
金额：
$ 57.54万
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/8864786
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 Enzymes Extracellular Matrix Family Fukuyama syndrome Functional disorder Genes Goals Hippocampus (Brain)Individual Investigational Therapies Knockout Mice Language Lead Learning Learning Disabilities Link Mannose Memory impairment Mental Retardation Methods Mus Mutate Mutation N-Acetylglucosaminyltransferases Neuroglia Neurologic Dysfunctions Neuronal Migration Disorder Neurons Neurophysiology - biologic function Outcome Patients Polysaccharides Problem Solving Prosencephalon Proteins Recovery Recovery of Function Role Serotyping Staging Structural defect Structure Symptoms Synapses Synaptic plasticity Technology Testing Therapeutic Transferase Vertebral column Viral Vector adeno-associated viral vector alpha Dystroglycan base 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 public health relevance relating to nervous system 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.