Abnormal Interleukin 1-B Inflammasome Activation and Epilpesy Surgery Outcomes

白细胞介素 1-B 炎症小体激活异常与癫痫手术结果

• 批准号: 9387161
• 负责人: Lara Jehi
• 金额: $ 27.38万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387161
• 关键词: 3-Dimensional; Acute; Adult; Beds; Binding; Biological Markers; Blood - brain barrier anatomy; Blood Tests; Brain; Brazil; Chronic; Clinic; Collaborations; Collection; Data; Development; Electroencephalography; Electron Microscopy; Electrophysiology (science); Enrollment; Ensure; Epilepsy; Epileptogenesis; Excision; Family; Foundations; Freedom; Freezing; Future; Gelatinase B; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Grant; Hour; Human; IL8 gene; Individual; Inflammasome; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-18; Lead; Lesion; Levetiracetam; Link; Lobe; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Microglia; Multiprotein Complexes; Mus; Neurons; Nucleotides; Operative Surgical Procedures; Outcome; Patients; Pattern; Perioperative; Postoperative Period; Predictive Value; Presynaptic Terminals; Prospective cohort; Proteins; RNA; Recurrence; Research; Research Infrastructure; Research Personnel; Resected; Resources; Retrospective cohort; Risk; Role; Seizures; Serum; Signal Transduction; Single Nucleotide Polymorphism; Site; Stimulus; Temporal Lobe Epilepsy; Testing; Time; TimeLine; Tissues; Translating; Universities; Work; brain surgery; brain tissue; clinical care; differential expression; genetic variant; healing; improved; innovation; marenostrin; neuroimaging; neuroinflammation; primary outcome; receptor; response; secondary outcome; time use; tool; transcriptome sequencing

Project Summary: Seizures recur in 50% of patients after temporal lobe epilepsy surgery and in 60%-70% after extra-temporal lobe epilepsy surgery. An exclusive focus on refining “epilepsy localization” has not yet drastically improved seizure outcomes. We recently proposed that de-novo epileptogenesis in genetically predisposed patients may influence “late” recurrences first manifesting after months to years of postoperative seizure-freedom. Evidence is accruing on neuro-inflammation's role in epilepsy, and genetic variation in Interleukin-1β (IL-1β) expression was linked to the risk of posttraumatic human epilepsy. We will explore the central hypothesis that genetic variability in IL- 1β and its related inflammasome translates into an altered pattern of microglial activation after epilepsy surgery, facilitating subsequent epileptogenesis in brain tissue at the edge of the resection and later seizure recurrence. Time to first seizure recurrence is our primary outcome. Spikes on 6-month postoperative EEG in patients who were seizure-free up to that point is our secondary outcome. In Specific Aim 1, we retrospectively explore the relationship between seizure outcomes and genetic variability in IL-1β and related inflammasome activation in resected epileptic brain tissue. We focus on SA1a)- the SNP) rs1143634 IL-1β gene variant ; and SA1b)- activation of the multi-protein complex controlling the synthesis of IL- 1β [the nucleotide binding and oligomerization domain like receptor family pyrin domain-containing 3(NLRP3)inflammasome], as measured by RNA/protein extraction of inflammasome components and their immunohistochemical localization to microglia. In Specific Aim 2, we explore the relationship between MRI signatures of peri-operative neuroinflammation and postoperative epileptogenesis using brain MRI done in the University of Campinas 24-72 hours after surgery. In Specific Aim 3, we expand the questions of SA1 and 2 using a prospective cohort of 25 patients enrolled from Mayo Clinic and Cleveland Clinic as we (SA3a) determine if peri-operative serum measurements of IL-1β, MMP-9, or IL-18 correlate with the primary and secondary outcome, and identify the ideal collection time to study in a future definitive project; (SA3b) study the timeframe for development of our proposed postoperative epileptogenesis biomarkers; and (SA3c) explore our proposed mechanism by studying the relative (margin vs.core of resected epileptic tissue) degree of microglial activation, IL-1β tissue expression in those with favorable vs unfavorable outcomes. Our strong preliminary data support our hypothesis. The collaboration of multiple sites (Cleveland Clinic, Mayo Clinic, and University of Campinas) will indirectly test the feasibility and build infrastructure needed for a future definitive study. We take advantage of existing resources and a track record of productive collaborations among our investigators to optimize the efficiency of study conduct and ensure study completion. If successful, this work will open the door for an innovative line of research on surgical outcomes after epilepsy surgery with a significant potential for altering clinical care given the multitude of selective IL-1β modifiers on the market.

项目概要： 颞叶癫痫手术后 50% 的患者复发癫痫发作，颞叶外癫痫手术后 60%-70% 的患者复发癫痫发作 专注于完善“癫痫定位”的癫痫手术尚未显着改善癫痫发作。 我们最近提出，遗传易感性患者的新发癫痫可能会影响结果。 “晚期”复发在术后数月至数年无癫痫发作后首次出现。 神经炎症在癫痫中的作用，白介素 1β (IL-1β) 表达的遗传变异与 我们将探讨IL-基因变异的中心假设。 1β及其相关炎症小体转化为癫痫后小胶质细胞激活的模式 手术，促进切除边缘脑组织随后的癫痫发生 癫痫复发。首次癫痫复发的时间是术后 6 个月的峰值。 至此为止无癫痫发作的患者的脑电图是我们的次要结果。 在具体目标 1 中，我们回顾性探讨了癫痫发作结果与遗传变异之间的关系 我们重点关注 SA1a)- SNP)。 rs1143634 IL-1β 基因变体；和 SA1b)- 控制 IL- 合成的多蛋白复合物的激活 1β [核苷酸结合和寡聚化结构域，类似受体家族，含有pyrin结构域 3(NLRP3)炎症小体]，通过炎症小体成分及其RNA/蛋白质提取进行测量 在特定目标 2 中，我们探讨了 MRI 与小胶质细胞的免疫组织化学定位之间的关系。 使用 MRI 进行的围手术期神经炎症和术后癫痫发生的特征 坎皮纳斯大学手术后 24-72 小时 在具体目标 3 中，我们扩展了 SA1 和 的问题。 2 使用由 Mayo Clinic 和 Cleveland Clinic 招募的 25 名患者组成的前瞻性队列（SA3a） 确定围手术期血清 IL-1β、MMP-9 或 IL-18 测量是否与原发性和 次要结果，并确定在未来的最终项目（SA3b）中研究的理想收集时间； 我们提出的术后癫痫发生生物标志物的开发时间表；以及（SA3c）探索我们的研究； 通过研究小胶质细胞的相对（切除的癫痫组织的边缘与核心）程度提出了机制 激活、IL-1β 组织在有利与不利结果中的表达。 我们强有力的初步数据支持我们的假设。多个站点的合作（克利夫兰诊所、梅奥）。 诊所和坎皮纳斯大学）将间接测试可行性并建设未来所需的基础设施 我们利用现有资源和富有成效的合作记录。 我们的研究人员将优化研究进行的效率并确保研究顺利完成。 将为癫痫手术后手术结果的创新研究打开大门，具有显着的意义 鉴于市场上有多种选择性 IL-1β 修饰剂，改变临床护理的潜力。