Discovery of Novel Molecular Abnormalities Underlying Non-Lesional Focal Epilepsy

发现非病变局灶性癫痫背后的新型分子异常

• 批准号: 9109076
• 负责人: Peter B Crino
• 金额: $ 31.93万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109076
• 关键词: Affect; Anticonvulsants; Area; Autopsy; Base Sequence; Biological; Biological Markers; Brain; Cells; Cervical; Clinical; Collaborations; Collection; Copy Number Polymorphism; Cortical Dysplasia; DNA; Data; Data Set; Detection; Development; Early Diagnosis; Electrocorticogram; Epilepsy; Epileptogenesis; Evaluation; Excision; Functional disorder; Genes; Genome; Genomics; Goals; Health; Histopathology; Human Herpesvirus 6; Human Papillomavirus; Image; Individual; Infection; Intractable Epilepsy; Lead; Lesion; Leukocytes; Magnetic Resonance Imaging; Malignant Neoplasms; Molecular; Molecular Abnormality; Molecular Sequence Data; Mutation; Neocortex; Nucleic Acids; Nucleic acid sequencing; Operative Surgical Procedures; Partial Epilepsies; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Play; Point Mutation; Population; Prevention; Property; RNA; Records; Recurrence; Research; Resected; Resolution; Resources; Role; Sampling; Sclerosis; Seizures; Somatic Mutation; Specificity; Specimen; Structural defect; Systems Biology; Techniques; Technology; Temporal Lobe Epilepsy; Testing; Tissue Sample; Tissues; Variant; Viral; Viral Proteins; Virus; Virus Diseases; base; brain cell; brain tissue; high risk; innovation; laser capture microdissection; malformation; member; microbial; mind control; multidisciplinary; nervous system development; new technology; next generation sequencing; novel; novel marker; novel strategies; pathogen; phenome; phenotypic data; repository; success; tissue registry; treatment strategy; viral detection

DESCRIPTION (provided by applicant): The goal of this proposal is to explore the role of molecular abnormalities-somatic mutation, the presence of microbial nucleic acids, or both--underlying non-lesion focal epilepsy (NLFE). Epilepsy affects nearly 1% of the world's population and 1/3 of patients do not respond to currently available anticonvulsant medications. For these patients the best hope for seizure control comes from epilepsy surgery with resection of the seizure focus, when a focus can be identified. In patients for whom a causative lesion is clearly demonstrable on MRI, 60-80% of patients are seizure-free after surgery. In patients with clear focal epilepsy with no identifiable MRI lesion, surgical cure is less common, ranging from 30-50%. We propose that the problem of NLFE is one of resolution-that the abnormalities may not be visible on MRI but are present at the molecular level, in one or both of two forms: 1) somatic mutation, in cells restricted to brain and 2) the presence of microbial, e.g. viral nucleic acids, which may cause molecular abnormalities and influence epilepsy onset. There is some evidence to suggest that somatic mutation plays a role in epilepsies resulting from developmental structural lesions such as hemimegalencephaly, but somatic mutation has not yet been shown to occur in non-lesion epilepsies. The role of viral infection in epilepsy and developmental molecular lesions of the cortex has been suggested based on the detection of HHV6 in brain tissue from temporal lobe epilepsy patients with mesial temporal sclerosis and with the recent discovery of human papilloma virus in areas of focal cortical dysplasia, a developmental malformation strongly associated with epilepsy. The broader role of viruses in NLFE has not been demonstrated, nor the role of other pathogens. We will investigate whether somatic mutations and microbial nucleic acids are present in the seizure foci of individuals with epilepsy who undergo surgery, using next generation sequencing approaches to identify these molecular abnormalities in resected brain tissue. We will accomplish this using a systems biology approach, integrating state-of-the-art cortical intraoperative recordings to identify the seizure focus, co-registered with clinical, histopathology, and molecular sequence data. We will thereby create a repository of NLFE brain tissue with detailed phenotypic data which will be the first of its kind. Proving that seizures can arise from somatic mutations or infection without altering brain macrostructure would shift the paradigm for understanding epileptogenesis, and could lead to identification of novel biomarkers and treatments.

描述（由申请人提供）：该提案的目的是探索分子异常 - 符合性突变，微生物核酸的存在或两者兼而有之 - 在非溶性局灶性局灶性癫痫（NLFE）下。癫痫会影响世界近1％的人口，其中1/3患者对当前可用的抗惊厥药物没有反应。对于这些患者，癫痫发作控制的最大希望来自癫痫手术，切除了癫痫发作的重点。在MRI上明显证明了病变的患者中，有60-80％的患者在手术后无癫痫发作。在没有可识别的MRI病变的明显局灶性癫痫的患者中，手术治愈不太常见，范围为30-50％。我们建议NLFE的问题是解决方案之一 - 在MRI上可能不见异常，而是在分子水平上以一种或两种形式存在于分子水平上：1）体细胞突变，限于大脑的细胞和2）微生物的存在，例如。病毒核 酸可能会导致分子异常并影响癫痫发作。有一些证据表明，体细胞突变在由hemimegalencephaly等发育结构病变引起的癫痫中起作用，但尚未证明体细胞突变发生在非静脉癫痫中。已经提出了病毒感染在皮质的癫痫和发育分子病变中的作用，这是基于颞叶癫痫患者的脑组织中HHV6的检测以及最近发现人类乳头状瘤病毒在局部皮质骨质肿瘤中与发育异常相关的人类乳头状瘤病毒的最新发现的作用。病毒在NLFE中的更广泛作用尚未得到证明，也没有其他病原体的作用。我们将使用下一代测序方法来鉴定切除的脑组织中的这些分子异常。我们将使用系统生物学方法来完成此操作，并整合最先进的皮质术中记录，以确定癫痫发作的焦点，并与临床，组织病理学和分子序列数据共同注册。因此，我们将创建一个NLFE脑组织的存储库，并具有详细的表型数据，这将是第一个。证明癫痫发作可能是由体细胞突变或感染引起的，而不会改变脑部宏结构会改变范式以理解癫痫发生，并可能导致对新型生物标志物和治疗的识别。