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.

项目概要癫痫是儿童和成人发病和死亡的常见且代价高昂的原因。发育和癫痫性脑病 (DEE) 是严重的儿童癫痫症，需要快速诊断才能启动控制癫痫发作并预防或逆转神经功能丧失的治疗。然而，这些癫痫发作通常对药物没有反应。大多数 DEE 患者预计有已知的潜在疾病遗传病因学，但它们往往缺乏分子诊断，因为潜在的致病变异存在于尚未与神经功能障碍相关的基因。我们已经发现了新的变异患有发育迟缓、DEE、视力异常以及某些大脑结构异常的患者中的 MAST4 基因异常。 MAST4 是正在研究的丝氨酸苏氨酸激酶家族（MAST1-4 和 MAST 样）属于 IDG 合格蛋白质之一，具有作为治疗药物影响人类健康的巨大潜力癫痫的目标。在目标 1 中，我们将描述神经发育中 MAST4 时空表达的特征，使用无标记质谱法识别体内 MAST4 相互作用蛋白。在目标 2 中，我们将验证 MAST4 相互作用蛋白以及患者特异性突变对原发性中这些相互作用的影响体外培养的神经元。这些实验的结果将提供重要的功能数据和为具有 MAST4 突变的 DEE 患者指导精准医疗之路的工具。