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; 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.

项目摘要： 临时叶癫痫手术后50％的患者中的癫痫发作在循环大叶后60％-70％复发 癫痫手术。专注于完善“癫痫定位”的专注尚未大大改善癫痫发作 结果。我们最近提出，遗传性易感患者中的脱氧疫苗发生可能会影响 “迟到”是在术后癫痫发作 - 自由的数月到数年后首次恢复。证据正在累积 关于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 创伤后人类癫痫的风险。我们将探讨一个中心假设，即IL-遗传变异性 1β及其相关的炎性体转化为癫痫后的小胶质细胞激活模式 手术，支持切除边缘的脑组织中随后的癫痫发生，然后 癫痫发作复发。首次癫痫发作复发的时候是我们的主要结果。术后6个月的峰值 到那时，无癫痫发作的患者的脑电图是我们的次要结果。 在特定目标1中，我们回顾性地探索癫痫结局与遗传变异性之间的关系 在切除的癫痫脑组织中IL-1β和相关的炎性体激活中。我们专注于sa1a） - SNP） RS1143634 IL-1β基因变体；和SA1B） - 控制IL-合成的多蛋白质复合物的激活 1β[核苷酸结合和寡聚结构域，例如受体家族pyrin结构域 3（nlrp3）炎性体]，通过RNA/蛋白质提取的炎性组成分及其蛋白质及其 免疫组织化学对小胶质细胞的定位。在特定目标2中，我们探索MRI之间的关系 使用大脑MRI在 手术后24-72小时，坎皮纳斯大学。在特定目标3中，我们扩展了SA1和 2使用我们（SA3A）的25名患者组成的前瞻性队列（SA3A） 确定IL-1β，MMP-9或IL-18的围手术期血清测量是否与初级和 次要结果，并确定未来确定项目中学习的理想收集时间； （SA3B）研究 开发我们提出的术后癫痫生成生物标志物的时间范围； （SA3C）探索我们的 通过研究小胶质细胞的相对（切除癫痫组织的边缘与切除的癫痫组织的核）提出的机制 激活，IL-1β组织表达在有利与不利结果的人中。 我们强大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Campinas大学）将间接测试可行性并建立未来所需的基础设施 确定研究。我们利用现有资源和产品合作的记录 我们的研究人员以优化研究行为的效率并确保完成研究。如果成功，这项工作 将为癫痫手术后的手术结局进行创新的研究开辟大门 鉴于市场上有多种选择性IL-1β修饰符，改变临床护理的可能性。