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:
- 金额:$ 57.54万
- 依托单位:
- 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:
- 关键词:AdultAnimal ModelAnimalsArchitectureBindingBiochemicalBirthBrainCellsCobblestone LissencephalyCognitiveCognitive deficitsCre-LoxPDataDefectDendritic SpinesDevelopmentDiseaseDystroglycanECM receptorEnzymesExtracellular MatrixFamilyFukuyama syndromeFunctional disorderGenesGoalsHippocampus (Brain)IndividualInvestigational TherapiesKnockout MiceLanguageLeadLearningLearning DisabilitiesLinkMannoseMemory impairmentMental RetardationMethodsMusMutateMutationN-AcetylglucosaminyltransferasesNeurogliaNeurologic DysfunctionsNeuronal Migration DisorderNeuronsNeurophysiology - biologic functionOutcomePatientsPolysaccharidesProblem SolvingProsencephalonProteinsRecoveryRecovery of FunctionRoleSerotypingStagingStructural defectStructureSymptomsSynapsesSynaptic plasticityTechnologyTestingTherapeuticTransferaseVertebral columnViral Vectoradeno-associated viral vectoralpha Dystroglycanbasebrain malformationcongenital muscular dystrophydensitydesigndystroglycanopathyeffective therapyfunctional improvementfunctional plasticitygene replacement therapygene therapygenetic approachglycosylationglycosyltransferaseimprovedinterestknockout genemental functionmouse modeloverexpressionpostnatalpreventprotein expressionprotein-O-mannosyltransferase 2public health relevancerelating to nervous systemresearch studyrestorationskillssugartherapeutic 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(由申请人提供):肌营养不良症是一组先天性肌营养不良症,涉及脑畸形和严重智力障碍,大多数已确定的原因是糖基转移酶突变,导致α-肌营养不良症(一种细胞外基质受体)糖基化低。包括 II 型无脑畸形的特征是一种神经元迁移障碍,目前尚无有效的治疗方法。该项目的长期目标是开发治疗基因策略来改善大脑功能,尽管异常的大脑结构被认为是导致神经功能障碍和疾病的最关键因素,但我们最近的研究提供了令人信服的结果。
有证据表明,许多关键神经功能更关键地依赖于成人大脑中持续的糖基化,特别是我们发现,空间学习不足主要是由于细胞-ECM 相互作用缺陷导致树突棘可塑性改变造成的,而糖基化的恢复可以恢复脊柱。尽管组织学结构异常,但出生后基因治疗仍可恢复脊柱可塑性并改善大脑功能。该提案重点关注其机制。空间学习缺陷及其通过基因治疗的挽救,作为改善营养不良症心理功能的第一步。具体目标是了解基因治疗的空间学习缺陷和功能恢复的机制。脊柱可塑性导致空间学习缺陷
目标 2:确定尽管存在脑畸形,但通过基因治疗恢复 α-肌营养不良症糖基化是否可以挽救肌营养不良症的空间学习缺陷。使用组织学、电生理学、生物化学和最先进的遗传学方法来研究迁移障碍本身将提高对疾病的认识。预计将产生实验性疗法。针对出生后可塑性缺陷而不是纠正发育组织学缺陷的基因治疗策略可能广泛用于其他神经元迁移障碍。
项目成果
期刊论文数量(0)
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HUAIYU HU其他文献
HUAIYU HU的其他文献
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Mechanisms of cognitive deficits in dystroglycanopathies
肌营养不良症认知缺陷的机制
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Mechanisms of cognitive deficits in dystroglycanopathies
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