Manipulating temporal and spacial CaMKII activity in Angelman Syndrome

操纵天使综合征中的时空 CaMKII 活性

基本信息

批准号：
8131109
负责人：
Edwin John Weeber
金额：
$ 18.01万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-20 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8131109
关键词：
Ablation Acute Adult Angelman Syndrome Area Ataxia Autistic Disorder Bilateral Biochemical Brain Brain region Calcium Chromosomes Chromosomes, Human, Pair 15 Cognition Disorders Cognitive Defect Disease Effectiveness Elderly Engineering Enhancers Etiology Exhibits Fathers Frequencies Functional disorder Future Gene Expression Genes Genetic Genetic Predisposition to Disease Goals Hippocampus (Brain)Human Human Development Impaired cognition Independent Living Individual Inherited Injection of therapeutic agent Intervention Laboratories Measures Mental Retardation Molecular Molecular Abnormality Molecular Target Mothers Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Paternal uniparental disomy Phenotype Phosphorylation Pilot Projects Population Prevalence Proteins Rett Syndrome Seizures Site Slice Speech Stream Synapses Synaptic plasticity Testing Therapeutic Therapeutic Human Experimentation Therapeutic Intervention Threonine Time Virus Work base calmodulin-dependent protein kinase II classical conditioning design fusion gene gene replacement imprint maternal imprint mouse model nervous system disorder particle postnatal pre-clinical public health relevance receptor receptor function reelin protein restoration synaptic function virtual

项目摘要

DESCRIPTION (provided by applicant): Angelman Syndrome (AS) is a genetic neurological disorder that presents with seizure, ataxia, severe mental retardation, virtual absence of speech, and is genetically and biochemically associated with other cognitive disorders, such as autism and Rett syndrome. AS is caused by inactivation of the UBE3A gene in the brain due to various abnormalities of the 15q11-q13 chromosome inherited from the mother, including: a deletion of the region q11.2-q13 on the maternally inherited chromosome 15; a mutation in the UBE3A gene; paternal uniparental disomy in which the father contributes both copies of chromosome 15; an imprinting defect; or through an as yet unidentified mechanism. Work in our laboratory has centered upon identifying a molecular basis for the disease that lies downstream of UBE3A maternal deficiency. We recently demonstrated that genetic ablation of the auto-inhibitory site of 1CaMKII can rescue the major phenotypes of the Ube3a m-/p+ mouse. These results suggest that the major site of biochemical dysfunction in the AS mouse model is down- stream of CaMKII. This project is designed with the ultimate goal of establishing the basis for future rational development of human AS interventions. We present evidence which indicates that AS is potentially a treatable disorder. This exciting possibility is experimentally testable due in large part to the extraordinary utility of the Ube3a m-/p+ mouse model. We have developed three distinct therapeutic interventions to determine if the Ube3a m-/p+ mouse model phenotype can be rescued in a postnatal fashion through intervention (1) at the site of genetic abnormality, (2) at the downstream biochemical site of dysfunction, or (3) by directly modifying synaptic function. Our goal is to establish the preclinical viability of these therapeutic strategies, determine the temporal constraints for treatment and identify the optimal molecular targets for future human therapeutic research. PUBLIC HEALTH RELEVANCE: Angelman Syndrome (AS) is a genetic neurological disorder occurring in one in 12,000 populations. Independent living is not possible for adults with AS. The goals of this project are to establish the viability of three distinct therapeutic strategies to ameliorate the severe cognitive impairments exhibited by AS individuals.

描述（由申请人提供）：天使综合征（AS）是一种遗传性神经系统疾病，表现为癫痫、共济失调、严重智力低下、几乎无法言语，并且在遗传和生化方面与其他认知障碍（例如自闭症和雷特综合征）相关。 AS是由于从母亲遗传的15q11-q13染色体的各种异常导致大脑中UBE3A基因失活而引起的，包括：母系遗传的15号染色体上q11.2-q13区域的缺失； UBE3A 基因突变；父系单亲二体性，其中父亲贡献了 15 号染色体的两个拷贝；压印缺陷；或通过一种尚未确定的机制。我们实验室的工作重点是确定 UBE3A 母体缺陷下游疾病的分子基础。我们最近证明，1CaMKII 自身抑制位点的基因消除可以挽救 Ube3a m-/p+ 小鼠的主要表型。这些结果表明 AS 小鼠模型中生化功能障碍的主要部位是 CaMKII 的下游。该项目的最终目标是为人类 AS 干预措施的未来合理发展奠定基础。我们提供的证据表明 AS 可能是一种可治疗的疾病。这种令人兴奋的可能性可以通过实验进行测试，这在很大程度上要归功于 Ube3a m-/p+ 小鼠模型的非凡实用性。我们开发了三种不同的治疗干预措施，以确定 Ube3a m-/p+ 小鼠模型表型是否可以通过干预（1）遗传异常部位，（2）下游生化功能障碍部位，或(3)通过直接修改突触功能。我们的目标是确定这些治疗策略的临床前可行性，确定治疗的时间限制，并确定未来人类治疗研究的最佳分子靶点。公共健康相关性：天使综合症 (AS) 是一种遗传性神经系统疾病，每 12,000 个人中就有一人患有这种疾病。患有 AS 的成年人不可能独立生活。该项目的目标是确定三种不同治疗策略的可行性，以改善 AS 个体表现出的严重认知障碍。