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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：
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.

项目总结