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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：
9367494
负责人：
SCOTT H SODERLING
金额：
$ 49.32万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9367494
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 Modeling 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 excitatory neuron experimental study follow-up genetic approach genome editing gephyrin in vivo induced pluripotent stem cell 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，癫痫影响大约230万成年人和45万儿童。每个每年有15万公民被新诊断患有癫痫。估计费用与癫痫相关的医疗费用约为155亿美元，收益（NINDS）。治疗癫痫相关疾病的进展严重由于我们缺乏与分子机制相关的基本知识，潜在的紊乱我们最近发表在《科学》杂志上的研究，化学遗传学方法鉴定抑制性突触后蛋白质组（iPSD）。这项研究得到了R21的支持，并确定了一个大的蛋白质复合物，在兴奋性神经元的GABA能突触的iPSD处富集。其中一些是由已知人类突变引起的基因编码的新蛋白质癫痫这项赠款的具体目标建立在这些令人兴奋的发现和后续行动的基础上我们最近的研究集中在癫痫相关的可检验的假设，编码iPSD蛋白质的基因突变通过损害抑制作用我们期望这些目标的结果将弥合我们的知识差距关于癫痫如何在体内从异常的抑制，导致新的未来方向的预防和可能的治疗，这些紊乱。