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Analysis of Inhibitory Synaptic Proteins Associated with Brain Disorders

与脑部疾病相关的抑制性突触蛋白分析

基本信息

批准号：
10176611
负责人：
SCOTT H SODERLING
金额：
$ 48.94万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176611
关键词：
Adult Affect Brain Brain Diseases Cells Child Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Electroencephalography Electrophysiology (science)Epilepsy Etiology Excitatory Postsynaptic Potentials Excitatory Synapse Foundations Functional disorder Future GNAQ gene Genes Genetic Goals Grant Human Impairment Inhibitory Synapse Intellectual functioning disability Knowledge Label Lead Link Measures Mediating Medical Membrane Potentials Molecular Mus Mutation National Institute of Neurological Disorders and Stroke Neonatal Neurons Neurophysiology - biologic function Newly Diagnosed Online Mendelian Inheritance In Man Pathogenicity Pathologic Pathway interactions Physiological Predisposition Prevention Proteins Proteome Proteomics Publishing Role Science Seizures Site Structure Sturge-Weber Syndrome Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Work autism spectrum disorder base collybistin cost estimate excitatory neuron experimental study follow-up genetic approach genome editing gephyrin human model in vivo insight link protein loss of function mutation lost earning mutant novel postsynaptic protein complex repaired synaptic function synaptic inhibition synaptogenesis

项目摘要

Epilepsy affects approximately 2.3 million adults and 450,000 children in the US. Each year, 150,000 citizens are newly diagnosed with epilepsy. The estimated cost associated with epilepsies is approximately 15.5 billion in medical expenses and lost earnings (NINDS). Progress in treating disorders associated with epilepsies is severely hampered by our lack of basic knowledge related to the molecular mechanisms underlying the disorder. Our recently published work in Science, used a novel in vivo chemico-genetic approach to identify the proteome of the inhibitory postsynapse (iPSD). This study was supported by an R21 and identified a large complex of proteins that are enriched at the iPSD of GABAergic synapses of excitatory neurons. Several of these are novel proteins encoded by genes for which human mutations are known to cause epilepsies. The specific aims of this grant build on these exciting findings and follow up on our recent study by focusing on the testable hypothesis that epilepsy-associated mutations in genes encoding proteins of the iPSD lead to seizures by impairing inhibition. We anticipate the results of these aims will bridge our knowledge gap regarding molecular mechanisms of how epilepsies emerge in vivo from abnormalities of inhibition, leading to new future directions for the prevention and possible treatments of these disorders.

在美国，癫痫影响着大约230万成年人和45万儿童。每一个