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

利用 SHANK3 的翻译后调控作为 Phelan-McDermid 综合征的增强策略

基本信息

批准号：
10177755
负责人：
JIMMY L HOLDER
金额：
$ 53.7万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10177755
关键词：
2 year old Address Ankyrin Repeat Behavior Behavioral Biochemical Biochemistry Brain Caregivers Cells Clinical Cognitive Complex Data Development Developmental Delay Disorders Disease Economics Elements Epilepsy F-Box Proteins Future Gene Dosage Gene Mutation Genes Genetic Genomics Goals Half-Life Human In Vitro Individual Intellectual functioning disability Knockout Mice Knowledge Length Life MAPK1 gene Measures Mediating Methods Mission Molecular Mus Mutant Strains Mice Mutation National Institute of Neurological Disorders and Stroke Neurodevelopmental Disorder Neurons Pathogenicity Patients Pharmacology Phelan-McDermid syndrome Phenotype Phosphorylation Phosphotransferases Physiology Post-Translational Regulation Pre-Clinical Model Proteins Publishing Regulation Reporting Rodent Model Scaffolding Protein Symptoms Synapses Tertiary Protein Structure Testing Therapeutic Ubiquitination Work autism spectrum disorder base casein kinase casein kinase I dosage effective therapy family burden gain of function mutation improved in vivo inhibitor/antagonist insight loss of function mutation member multicatalytic endopeptidase complex neurophysiology personalized medicine pre-clinical protein complex protein degradation repaired severe intellectual disability synaptogenesis targeted treatment

项目摘要

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.

项目总结大脑的正常发育需要精确的突触形成关键基因的剂量。基因的改变通过功能缺失突变，如基因组缺失，或功能突变获得，如基因组复制，导致大约50%的蛋白质含量变化。这通常会造成毁灭性的对大脑发育和功能的影响。在一个例子中，显性的、功能丧失的突变由SHANK3基因编码的突触后支架蛋白导致严重的神经发育精神障碍，费兰-麦克德米德综合征。患有费兰-麦克德米德综合征的患者有中到重度智力残疾，通常在生命的头两年出现发育迟缓。目前没有针对这种疾病的靶向治疗。这项建议旨在调查山克3的S翻译后调节，以增加基础知识突触发育和生理，并为患有SHANK3突变的个体开发治疗途径。在这个提案中，生物化学、行为学和神经生理学的结合将被用来解决以下内容：1.确定体内抑制ERK2是否可以挽救由于 SHANK3单倍体功能不全。2.确定酪蛋白激酶抑制对SHANK3稳定性和功能和3.鉴定调节SHANK3稳定性的蛋白酶体元件。这项工作的影响将是通过翻译后理解SHANK3的动态调节机制，发展对费兰-麦克德米德综合征治疗途径的临床前洞察并开发一种分子方法来确定神经发育障碍的个性化治疗对剂量敏感基因的突变。