Harnessing post-translational regulation of SHANK3 as a boosting strategy for Phelan-McDermid syndrome

项目摘要 适当的大脑发育需要精确剂量的基因，这些基因对突触的形成至关重要。基因改变 通过功能缺失突变，如基因组缺失，或功能获得突变，如 基因组复制，导致蛋白质含量约50%的变化。这往往具有毁灭性的 影响大脑发育和功能。在一个实施例中，在基因组中的显性、功能丧失突变可以被抑制。 由SHANK3基因编码的突触后支架蛋白引起严重的神经发育障碍， 疾病，McDermid综合征。患有McDermid综合征的个体具有中度至重度 智力残疾，发育迟缓，通常在生命的头两年出现。目前没有 有针对性的治疗方法 该提案旨在研究SHANK3的翻译后调节，以增加对SHANK3的基础知识。 突触发育和生理学，并为具有SHANK3突变的个体开发治疗途径。 在这个建议中，生物化学，行为和神经生理学的组合将被用来解决 以下内容：1.确定ERK 2的体内抑制是否挽救了由于以下原因引起的分子和行为异常： SHANK3单倍不足。2.确定酪蛋白激酶抑制对SHANK3稳定性的影响， 功能和3。确定调节SHANK3稳定性的蛋白酶体元件。 这项工作的影响将是了解SHANK3通过翻译后表达的动态调节。 机制，发展临床前洞察治疗途径的治疗性治疗，为McDermid综合征 并开发一种分子方法，用于确定神经发育障碍的个性化治疗， 剂量敏感基因的突变。

PROJECT SUMMARY Proper brain development requires precise dosages of genes critical for synapse formation. Alterations of gene dosage through loss-of-function mutations, such as genomic deletions, or gain of function mutations, such as genomic duplications, result in approximately 50% change in protein content. This often has devastating consequences for brain development and function. In one example, dominant, loss-of-function mutations in the post-synaptic scaffolding protein encoded by the SHANK3 gene causes a severe neurodevelopmental disorder, Phelan-McDermid syndrome. Individuals with Phelan-McDermid syndrome have moderate to severe intellectual disability with developmental delays often noted in the first two years of life. There are currently no targeted therapies for this disorder. This proposal aims to investigate SHANK3’s post-translational regulation to add fundamental knowledge of synaptic development and physiology and develop treatment avenues for individuals with SHANK3 mutations. In this proposal, a combination of biochemistry, behavior and neurophysiology will be utilized to address the following: 1. Determine if in vivo inhibition of ERK2 rescues molecular and behavioral abnormalities due to SHANK3 haploinsufficiency. 2. Determine the impact of Casein Kinase inhibition on SHANK3 stability and function and 3. Identify the proteasomal elements which regulate SHANK3 stability. The impact of this work will be to understand the dynamic regulation of SHANK3 through post-translational mechanisms, develop pre-clinical insight into therapeutic treatment avenues for Phelan-McDermid syndrome and develop a molecular approach for identifying personalized therapies for neurodevelopmental disorders due to mutations in dosage sensitive genes.