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Defining the MAST4 interactome in brain development and epilepsy

定义大脑发育和癫痫中的 MAST4 相互作用组

基本信息

批准号：
10664122
负责人：
Kimberly Anne Aldinger
金额：
$ 21.22万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664122
关键词：
Adult Alzheimer&apos s Disease Axon Binding Biochemical Brain Brain region Candidate Disease Gene Cells Cellular Morphology Child Childhood Co-Immunoprecipitations Data Development Developmental Delay Disorders Eligibility Determination Epilepsy Family Future Genes Genetic Genetic Predisposition to Disease Growth Health Healthcare Human Immunohistochemistry Impairment In Vitro Individual Label Mass Spectrum Analysis Microtubules Molecular Diagnosis Morbidity - disease rate Morphology Mouse Protein Mus Mutation N-terminal Nervous System Physiology Neurologic Dysfunctions Neurons Pathogenicity Patients Pharmaceutical Preparations Phosphotransferases Property Protein-Serine-Threonine Kinases Proteins Proteomics Rattus Reagent Resources Seizures Societies Synapses Testing Transcript Validation Variant Vision Western Blotting autism spectrum disorder brain abnormalities causal variant childhood epilepsy cortical visual impairment cost de novo mutation drug development epileptic encephalopathies experimental study genetic disorder diagnosis human fetal brain in vivo member mortality mutant nervous system disorder neurodevelopment neuroimaging precision medicine prevent protein expression quantitative imaging rapid diagnosis screening spatiotemporal therapeutic target tool

项目摘要

PROJECT SUMMARY Epilepsy is a common and costly cause of morbidity and mortality in children and adults. Developmental and epileptic encephalopathies (DEEs) are severe childhood epilepsies that require rapid diagnosis to initiate treatment that will control seizures and prevent or reverse the loss of neurologic function. However, these seizures often do not respond to medications. Most DEE patients are expected to have a known underlying genetic etiology, but they often lack a molecular diagnosis because the potential pathogenic variants are in genes that have not yet been associated with neurological dysfunction. We have identified de novo variants in the MAST4 gene in patients with developmental delay, DEE, vision abnormalities, and in some, structural brain abnormalities. MAST4 is a member of an understudied family of serine threonine kinases (MAST1-4 and MAST-like) that is among the IDG-eligible proteins with high potential to impact human health as a therapeutic target for epilepsy. In Aim 1, we will characterize MAST4 spatiotemporal expression in neurodevelopment and identify MAST4 interacting proteins in vivo using label-free mass spectrometry. In Aim 2, we will validate MAST4 interacting proteins and the impact of patient-specific mutations on these interactions in primary cultured neurons in vitro. The results from these experiments will provide both important functional data and tools to instruct the path to precision medicine for DEE patients with MAST4 mutations.

项目总结