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The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia

昼夜节律分子钟是局灶性皮质发育不良中癫痫的生物标志物

基本信息

批准号：
10625052
负责人：
Judy Shih-Hwa Liu
金额：
$ 8.16万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10625052
关键词：
Acidic Amino Acids Biological Markers Brain Brain region Caring Cell Line Cells Circadian gene expression Clinical Cortical Dysplasia Cortical Malformation Data Defect Development Disease Electrophysiology (science)Enhancers Epilepsy Epileptogenesis Excision Exhibits Frequencies Functional disorder Gene Expression Gene Expression Profiling Genes Genetic Genetic Techniques Genetic Transcription Goals Human Intractable Epilepsy Lead Magnetic Resonance Imaging Maintenance Measures Mediating Medical Messenger RNA Molecular Molecular Profiling Morbidity - disease rate Mus Neurons Neurosurgeon Operative Surgical Procedures Output Partial Epilepsies Pathway interactions Patients Procedures Proline Proteins Refractory Reporting Research Sampling Seizures Severities Statistical Data Interpretation Testing Therapeutic Tissue Sample Tissues Tuberous Sclerosis Validation Vertebral column bZIP Domain base brain abnormalities brain tissue childhood epilepsy circadian cohort excitatory neuron experimental study hippocampal pyramidal neuron human tissue improved inhibitory neuron loss of function malformation molecular clock mortality mouse genetics neuronal circuitry novel marker novel strategies novel therapeutic intervention optogenetics patch clamp personalized approach postsynaptic prevent profiles in patients restoration side effect small molecule therapeutic target transcription factor transcriptome

项目摘要

Scientific Abstract: A common heterogeneous non-inherited condition, focal cortical dysplasia (FCD), is the most common cause of refractory focal epilepsy. While FCD is presumably a stable developmental malformation, epilepsy onset is variable and cases of non-epileptogenic FCD are reported. What factors initiate epilepsy in FCD are unknown. Nevertheless, in pediatric epilepsy most therapeutic resections are performed for FCD patients with severely medically refractory seizures. The tissue collected from this procedure allowed us to study epileptogenesis in these cortical malformations. To discover molecular pathways and to identify potential therapeutic targets in epilepsy, we banked resections and performed a transcriptome analysis of the epileptogenic tissue from FCD and a related disorder Tuberous Sclerosis Complex (TSC). Our preliminary transcriptome analysis on surgical samples from intractable focal epilepsy surgical cases included patients with focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). The statistical analysis of gene expression in that study identified a decrease in the mRNA levels of the transcription factor, Circadian Locomotor Output Cycles Kaput (Clock), expression in epileptogenic tissue from both FCD and TSC compared with non-epileptic brain. This result was confirmed by Western analysis in a larger cohort of FCD cases. We found a reduction of Clock in both excitatory and inhibitory neurons. We created mouse lines with selective deletion of Clock in either excitatory neurons in the cortex or inhibitory neurons. We found that mice with specific deletion of the Clock gene in excitatory neurons have spontaneous seizures. Based on these results we hypothesize loss of Clock disrupts downstream gene expression leading to circuit dysfunction and epilepsy. Conversely, maintenance of Clock function prevents circuit and molecular changes causative for epilepsy. We will test this hypothesis in three aims: 1) We will determine the effect of Clock loss of function on cortical microcircuits. 2) We will determine a molecular mechanism for Clock by studying its targets, the PARbZip transcription factors. 3) We will use small molecule modifiers of circadian transcription genetic techniques to rescue the effects of decreased Clock. This approach has the potential to improve epilepsy care by developing new therapeutic strategies and refining epilepsy biomarkers.

摘要：局灶性皮质发育不良（FCD）是一种常见的异质性非遗传性疾病