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：
10589925
负责人：
JIMMY L HOLDER
金额：
$ 52.11万
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/10589925
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 Heterozygote 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 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 candidate identification casein kinase casein kinase I dosage effective therapy family burden gain of function mutation improved in vivo inhibitor insight loss of function mutation member multicatalytic endopeptidase complex neurophysiology personalized medicine pharmacologic postsynaptic 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.

项目概要正确的大脑发育需要对突触形成至关重要的基因的精确剂量。通过功能丧失突变（例如基因组缺失）或功能获得突变（例如基因组重复会导致蛋白质含量发生大约 50% 的变化，这通常具有毁灭性。在一个例子中，显性的功能丧失突变对大脑发育和功能产生影响。 SHANK3 基因编码的突触后支架蛋白会导致严重的神经发育障碍患有 Phelan-McDermid 综合征的个体患有中度至重度。出生后两年内经常出现的伴有发育迟缓的智力障碍目前还没有。针对这种疾病的靶向治疗。该提案旨在研究 SHANK3 的翻译后调控，以增加以下方面的基础知识：突触发育和生理学，并为 SHANK3 突变个体开发治疗途径。在该提案中，将结合生物化学、行为学和神经生理学来解决如下： 1. 确定 ERK2 的体内抑制是否可以挽救由于以下原因导致的分子和行为异常： SHANK3 单倍体不足 2. 确定酪蛋白激酶抑制对 SHANK3 稳定性和稳定性的影响。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了解 SHANK3 的动态调控机制，开发对 Phelan-McDermid 综合征治疗途径的临床前洞察并开发一种分子方法来识别因神经发育障碍而导致的个性化治疗剂量敏感基因的突变。