Manipulating temporal and spacial CaMKII activity in Angelman Syndrome

描述(申请人提供)：Angelman综合征(AS)是一种遗传性神经疾病，表现为癫痫、共济失调、严重的智力低下和虚拟的语言障碍，在遗传和生化方面与其他认知障碍有关，如自闭症和Rett综合征。UBE3A基因的失活是由于母亲遗传的15q11-q13染色体的各种异常导致的，包括：母亲遗传的15号染色体上q11.2-q13区域的缺失；UBE3A基因的突变；父亲贡献了15号染色体的两个副本的父系单亲二体；印记缺陷；或原因不明。我们实验室的工作重点是确定该疾病的分子基础，该疾病位于UBE3A母体缺陷的下游。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。这些结果表明，AS小鼠模型中生化功能障碍的主要部位是CaMKII的下游。本项目设计的最终目标是为人类作为干预措施的未来理性发展奠定基础。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小鼠模型的非凡实用性。我们已经开发了三种不同的治疗干预措施来确定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)通过直接改变突触功能而在出生后被挽救。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，并为未来的人类治疗研究确定最佳的分子靶点。 公共卫生相关性：安杰曼综合症(AS)是一种遗传性神经疾病，每12,000人中就有一人发生。患有强直性脊柱炎的成年人无法独立生活。这个项目的目标是建立三种不同的治疗策略的可行性，以改善AS个体所表现出的严重认知障碍。

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.