Manipulating temporal and spacial CaMKII activity in Angelman Syndrome

描述（由申请人提供）：Angelman综合征（AS）是一种遗传性神经系统疾病，表现为癫痫发作、共济失调、严重智力迟钝、几乎无法说话，并与其他认知障碍（如自闭症和Rett综合征）在遗传和生物化学上相关。AS是由遗传自母亲的15q11-q13染色体的各种异常导致大脑中UBE3A基因失活引起的，包括：母亲遗传的15号染色体上q11-q13区域的缺失；UBE3A基因突变；父亲单亲二体，父亲提供15号染色体的两个副本；印迹缺陷；或者通过一种尚未确定的机制。我们实验室的工作集中在确定UBE3A母系缺陷下游疾病的分子基础上。我们最近证明，基因消融1CaMKII的自身抑制位点可以挽救Ube3a m-/p+小鼠的主要表型。这些结果提示，AS小鼠模型生化功能障碍的主要部位位于CaMKII下游。本项目设计的最终目标是为未来人类AS干预措施的合理发展奠定基础。我们提出的证据表明，AS是一种潜在的可治疗的疾病。这种令人兴奋的可能性在实验上是可以测试的，这在很大程度上要归功于Ube3a m-/p+小鼠模型的非凡效用。我们已经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)在遗传异常部位，(2)在功能障碍的下游生化部位，或(3)通过直接修改突触功能以产后方式恢复。我们的目标是建立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。

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.